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THE ALKALOIDS Chemistry and Physiology

Volume XVIII

This Page Intentionally Left Blank

THE ALKALOIDS Chemistry and Physiology Foutzding Editor

R. H. F. MANSKE Edited by

R. G. A . RODRIGO Wilfrid Laurier University Wrrrerloo, Ontario, Canudu

VOLUME XVIII

1981 ACADEMiC PRESS NEW YORK

0

LONDON

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TORONTO

0

SYDNEY

0

SAN FRANCISCO

A Subsidiary of Harcourt Brace Jovanovich, Publishers

COPYRIGHT @ 1981, BY ACADEMIC PRESS,INC. ALL RIGHTS RESERVED. NO PART O F THIS PUBLICATION MAY BE REPRODUCED OR TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT PERMISSION I N WRITING F R OM T HE PUBLISHER.

ACADEMIC PRESS, INC.

111 Fifth Avenue, New York, New York 10003

United Kingdom Edition published by ACADEMIC PRESS, INC. (LONDON) LTD. 24/28 Oval Road, London N W l

IDX

L i b r a r y o f Congress Cataloging i n P u b l i c a t i o n Data Manske, Richard k l r m t h Fred, Date. The a l k a l o i d s ; chemistry and physioloqy. Vols. 8-16 e d i t e d by R. H. F. Manske. v o l s . 17e d i t e d by R . H. F. Manske, R . G . A. Rogrigo. Includes bibliographical references. 1. Alkaloids. 2 . Alkaloids--Physiological e f f e c t . I . tblmes, Henry Lavergne, j o i n t a u t h o r . 11. Title: Thru physiology. W421. M3 547.7'2 ISBN 0-12-469518-3 ( v . 18)

50-5522 AACRl

PRINTED IN THE UNITED STATES OF AMERICA 81 82 83 84

9 8 7 6 5 4 3 2 1

CONTENTS LISTOF CONTRIBUTORS . . . . . . . . . . . . . . . . . . . . . . . . . . PREFACE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CONTENTS OF PREVIOUS VOLUMES. . . . . . . . . . . . . . . . . . . . .

vii ix xi

Chapter 1. Erythrina and Related Alkaloids S. F . DYKEA N D S. N . QUESSY I . Introduction

. . . . . . . . . . . . . . . . . . . . . . . . . . .

I1 . Erythrina Alkaloids

. . . . . . . . . . . . . . . . . . . . . . . .

111. Homoerythrina Alkaloids IV. Cephalotaxus Alkaloids V. Biosynthesis . . . . . VI . Synthesis . . . . . . . VII . Pharmacology . . . . . References . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . .

1

2 27 42 51 61 91 93

Chapter 2. The Chemistry of Cz,. Diterpenoid Alkaloids S. WILLIAM PELLETIER A N D NARESH V. MODY

I . Introduction

. . . . . . . . . . . . . . . . . . . . . . . . . . .

I1 . Veatchine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . 111. Atisine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . IV. Bisditerpenoid Alkaloids . . . . . . . . . . . . . . . . . . . . . . V. Behavior and Formation of the Carbinolamine Ether Linkage in VI . VII . VIII . IX .

Diterpenoid Alkaloids: The Baldwin Cyclization Rules W-NMR Spectroscopy of CZrDiterpenoid Alkaloids Mass Spectral Analysis of Czo-Diterpenoid Alkaloids Synthetic Studies . . . . . . . . . . . . . . . . . A Catalog of CZo-DiterpenoidAlkaloids . . . . . . References . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . .

100

102 122 144 149 160 163 168 1% 211

Chapter 3 . The 'T-NMR Spectra of Isoquinoline Alkaloids D . W. HUGHESA N D D . B . MACLEAN I . Introduction

. . . . . . . . . . . . . . . . . . . . . . . . . . .

I1. 1,2,3,4 Tetrahydro and 3-4-Dihydroisoquinolines

111. Benzylisoquinoline Alkaloids

. IV. Bisbenzylisoquinoline Alkaloids V. Cularine . . . . . . . . . . VI . The Morphine Alkaloids . . .

. . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V

217 219 223 226 227 228

vi

CONTENTS

VII . Cancentrine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . VIII . Pavine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . IX . Aporphine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . X . Reduced and Nonreduced Proaporphines . . . . . . . . . . . . . . XI . Tetrahydroprotoberberine Alkaloids . . . . . . . . . . . . . . . . XI1 . Protopine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . XIII . Phthalideisoquinoline Alkaloids . . . . . . . . . . . . . . . . . . XIV. Modified Phthalideisoquinoline Alkaloids . . . . . . . . . . . . . . XV. Benzo[c]phenanthridie Alkaloids . . . . . . . . . . . . . . . . . XVI . Spirobenzylisoquinoline Alkaloids . . . . . . . . . . . . . . . . . XVII . Rhoeadine . . . . . . . . . . . . . . . . . . . . . . . . . . . . XVIII . Secoberbine Alkaloids . . . . . . . . . . . . . . . . . . . . . . . XIX . Emetine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . XX . Miscellaneous Alkaloids . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . .

.

. . . .

.

230 234 235 238 239 243 245 249 250 252 257 257 259 260 261

Chapter 4 . The Lythraceae Alkaloids W. MAREKGCKFBIEWSKI A N D JERZY T. WROBEL

I . Introduction . . . . . . . . . . . . . . . . . I1. Lactonic Biphenyl Alkaloids . . . . . . . . . . I l l . Lactonic Biphenyl Ether Alkaloids . . . . . . IV. Simple Quinolizidine Alkaloids . . . . . . . . V. Ester Alkaloids . . . . . . . . . . . . . . . . VI . Piperidine Metacyclophane Alkaloids . . . . . VII . Quinolizidine Metacyclophane Alkaloids . . . . VIII . Synthesis . . . . . . . . . . . . . . . . . . . IX . Biosynthesis . . . . . . . . . . . . . . . . . X . Physiological Activity . . . . . . . . . . . . . References .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . .

263 266 281 284 286 288 294 303 313 319 3 20

Chapter 5 . Microbial and in Vitro Enzymic Transformations of Alkaloids H . L . HOLLAND

I . Introduction . . . . . . . . . . . . . . . . . I1 . Enzymes Involved in Alkaloid Transformations 111. Transformations of Indole Alkaloids . . . . . IV. Transformations of Isoquinoline Alkaloids . . . V. Transformations of Pyridine Alkaloids . . . . . VI . Transformations of Pyrrolizidine Alkaloids . . . VII . Transformations of Quinoline Alkaloids . . . . VIII . Transformations of Steroidal Alkaloids . . . . IX . Transformations of Tropane Alkaloids . . . . . References . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

. . . .

. . . .

. . . .

. . . .

. . . .

. . . . . . . . . . . . . . . . . . . . . . . . . . .

INDEX. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

324 325 328 348 376 376 381 383 391 395 401

LIST OF CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors' contributions begin.

S. F. DYKE"( l ) , School of Chemistry, The University of Bath, Bath BA2 7AY, England W. MAREKG O K ~ B I E W (263), S K I Department of Chemistry, University of Warsaw, Warsaw 02-093, Poland (3231, Department of Chemistry, Brock University, St. H. L. HOLLAND Catharines, Ontario L2S 3A 1, Canada D. W. HUGHES(217), Department of Chemistry, McMaster University, Hamilton, Ontario LSS 4M1, Canada (217), Department of Chemistry, McMaster University, D. B. MACLEAN Hamilton, Ontario L8S 4M1, Canada NARESHV. MODY(99), Institute for Natural Products Research, Department of Chemistry, University of Georgia, Athens, Georgia 30602 S. WILLIAMPELLETIER (99), Institute for Natural Products Research, Department of Chemistry, University of Georgia, Athens, Georgia 30602 S. N. Q U E S S Y(l), ~ School of Chemistry, The University of Bath, Bath BA2 7AY, England JERZYT. WROBEL(263), Department of Chemistry, University of Warsaw, Warsaw 02-093, Poland

* Present address: Department of Chemistry, Queensland Institute of Technology, Brisbane, Queensland, Australia. f Present address: Research and Development Department, Riker Laboratories, Thornleigh, New South Wales, Australia. vii


PREFACE This volume of “The Alkaloids” presents timely reviews of three groups, the Erythrim, Lythraceae, and C,,-diterpenoid alkaloids. The chapters are organized in the traditional manner and cover all aspects of the recent chemistry of these groups. A useful catalogue of Czoditerpenoid alkaloids is also included. One chapter is devoted to a discussion of the I3Carbon spectra of benzylisoquinolines and the fifth chapter collects and reviews work on the microbial and it? cirro transformations of the alkaloids. Both subjects have attracted increasing attention in recent years. The editor wishes to thank the authors for their cooperation in making this volume possible. We hope that it will be as useful to researchers in alkaloid chemistry as the previous seventeen have been and we welcome advice or criticism from our readers.

R. G. A. RODRICO

ix


CONTENTS OF PREVIOUS VOLUMES Contents of Volume I CHAPTER 1 . Sources of Alkaloids and Their Isolation B Y R . H . F. MANSKE 2 . Alkaloids in the Plant B Y W . 0. JAMES . . . . . . . . . . . 3 . The Pyrrolidine Alkaloids B Y LEO MARION. . . . . . . . . 4 . Senecio Alkaloids B Y NELSONJ . LEONARD. . . . . . . . . 5 . The Pyridine Alkaloids B Y LEOM A R I O N . . . . . . . . . . 6 . The Chemistry of the Tropane Alkaloids B Y H . L . HOLMES. . 7 . The Strychnos Alkaloids B Y H . L . HOLMES. . . . . . . . .

. . . . .

1

. . . . . . . . . .

15

. . . .

. . . .

. . . .

. . . .

. . . .

91 107 165 271 375

Contents of Volume II 8.1.

8.11. 9. 10. 1 1. 12. 13. 14. I5.

The Morphine Alkaloids I B Y H . L . HOLMES . . . . . . . . . . . . . 1 The Morphine Alkaloids B Y H . L . HOLMESA N D ( I N PART) GILBERTSTORK 161 Sinomenhe B Y H . L . HOLMES. . . . . . . . . . . . . . . . . . . . 219 Colchicine BY J . W . COOKA N D J . D . LOUDON. . . . . . . . . . . . 261 Alkaloids of the Amaryllidaceae B Y J . W. COOKA N D J . D . LOUDON. . . 33 1 Acridine Alkaloids B Y J . R . PRICE . . . . . . . . . . . . . . . . . . 353 The Indole Alkaloids B Y LEO MARION . . . . . . . . . . . . . . . . 369 The Erythrina Alkaloids BY LEOMARION. . . . . . . . . . . . . . . 499 The Strychnos Alkaloids . Part I1 B Y H . L . HOLMES . . . . . . . . . . 513

Contents of Volume 111 16. The Chemistry of the Cinchona Alkaloids B Y RICHARD B. T U R N E R A N D R . B . WOODWARD . . . . . . . . . . . . . . . . . . . . . . 17 . Quinoline Alkaloids Other Than Those of Cinchona B Y H . T. OPENSHAW 18. The Quinazoline Alkaloids B Y H . T . OPENSHAW. . . . . . . . . . . . 19. Lupine Alkaloids B Y NELSONJ . LEONARD . . . . . . . . . . . . . . . 20 . The Imidazole Alkaloids B Y A . R . BATTERSBY A N D H . T. OPENSHAW. . 21 . The Chemistry of Solanum and Veratrum Alkaloids B Y V . FRELOG A N D .OJEGER . . . . . . . . . . . . . . . . . . . . . . . . . . 22 . P-Phenethylamines BY L . RETI . . . . . . . . . . . . . . . . . . . 23 . Ephreda Bases B Y L . RETI . . . . . . . . . . . . . . . . . . . . . 24 . The Ipecac Alkaloids B Y MAURICE-M.~RIE JANOT . . . . . . . . . . .

1

65 101 119 20 1 247 313 339 363

Contents of Volume IV 25 . The Biosynthesis of Isoquinolines B Y R . H . F. M.4NSKE . . . . . . 26. Simple Isoquinoline Alkaloids B Y L . RETI . . . . . . . . . . . .

xi

1

7

xii

C O N T E N T S OF P R E V I O U S V O L U M E S

CHAPTER 27 . Cactus Alkaloids B Y L . RETI . . . . . . . . . . . . . . . . . . 28 . The Benzylisoquinoline Alkaloids B Y ALFREDBURGER. . . . . . . 29. The Protoberberine Alkaloids B Y R . H . F . MANSKE A N D WAL .TER R . ASHFORD. . . . . . . . . . . . . . . . . . . . . . . . . . 30. The Aporphine Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . 31 . The Protopine Alkaloids BY R . H . F. MANSKE . . . . . . . . . . 32. Phthalideisoquinoline Alkaloids B Y JAROSLAV STAN€KA N D R . H . F. MANSKE . . . . . . . . . . . . . . . . . . . . . . . . . . 33 . Bisbenzylisoquinoline Alkaloids B Y MARSHALL KULKA. . . . . . . 34. The Cularine Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . 35 . a-Naphthaphenanthridine Alkaloids B Y R . H . F. MANSKE . . . . . 36. The Erythrophletcrn Alkaloids BY G . DALMA . . . . . . . . . . . 37 . The Aconitum and Delphinium Alkaloids B Y E . S. STERN . . . . .

. . . .

23 29

. .

77 119 147

. .

. . . . . .

. . . . . . . .

167 199 249 253 265 275

Contents of Volume V 38 . 39 . 40. 41 . 42. 43. 44. 45 . 46. 47 . 48 .

Narcotics and Analgesics B Y HUGOKRUEGER. . . . . . . . . . . . . Cardioactive Alkaloids BY E . L . MCCAWLEY. . . . . . . . . . . . . Respiratory Stimulants B Y MICHAEL J . DALLEMACNE. . . . . . . . . Antimalarials BY L . H . SCHMIDT . . . . . . . . . . . . . . . . . . Uterine Stimulants B Y A . K . REYNOLDS . . . . . . . . . . . . . . . Alkaloids as Local Anesthetics B Y THOMAS P. CARNEY . . . . . . . . Pressor Alkaloids BY K . K . CHEN . . . . . . . . . . . . . . . . . . Mydriatic Alkaloids BY H . R . ING . . . . . . . . . . . . . . . . . . Curare-like Effects B Y L . E . CRAIG . . . . . . . . . . . . . . . . . The Lycopodium Alkaloids B Y R . H . F . MANSKE . . . . . . . . . . . Minor Alkaloids of Unknown Structure BY R . H . F. MANSKE. . . . . .

1

79 109 141 163 211 229 243 259 265 301

Contents of Volume VI 1. 2. 3. 4. 5. 6. 7. 8. 9.

Alkaloids in the Plant B Y K . MOTHES . . . . . . . . . . . . . . . . The Pyrrolidine Alkaloids B Y LEO MARION. . . . . . . . . . . . . . Senecio Alkaloids B Y NELSONJ . LEONARD. . . . . . . . . . . . . . The Pyridine Alkaloids B Y LEO MARION . . . . . . . . . . . . . . . The Tropane Alkaloids BY G . FODOR . . . . . . . . . . . . . . . . . The Strychnos Alkaloids BY J . B . HENDRICKSON. . . . . . . . . . . The Morphine Alkaloids B Y GILBERTSTORK . . . . . . . . . . . . . Colchicine and Related Compounds BY W. C . WILDMAN. . . . . . . . Alkaloids of the Amaryllidaceae B Y W. C . WILDMAN . . . . . . . . .

1

31 35 123 145 179 219 247 289

Contents of Volume VII 10. The Indole Alkaloids BY J . E . SAXTON. . . . . . . . . . . . . . . . 11. The Eryrhrina Alkaloids BY V. BOEKELHEIDE . . . . . . . . . . . . . 12. winoline Alkaloids Other Than Those of Cinchona B Y H . T. OPENSHAW 13. The Quinazoline Alkaloids B Y H . T . OPENSHAW . . . . . . . . . . . . 14. Lupine Alkaloids B Y NELSONJ . LEONARD . . . . . . . . . . . . . .

1

201 229 247 253

C O N T E N T S OF P R E V I O U S V O L U M E S

CHAP^-ER 15. Steroid Alkaloids: The Holarrhena Group B Y 0 . JECERA N D V. PRELOG. 16. Steroid Alkaloids: The Solanum Group B Y V. PRELOGA N D 0. JEGER . . 17. Steroid Alkaloids: Verarrum Group B Y 0. JECERA N D V. PRELOC. . . . 18. The Ipecac Alkaloids B Y R . H . F. MANSKE. . . . . . . . . . . . . . 19. Isoquinoline Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . . . STANEK . . . . . . . . . 20. Phthalideisoquinoline Alkaloids B Y JAROSLAV 21. Bisbenzylisoquinoline Alkaloids B Y MARSHALL KULKA. . . . . . . . . 22. The Diterpenoid Alkaloids from Aconirum. Delphinium. and Garrya Species B Y E . S. STERN . . . . . . . . . . . . . . . . . . . . . . . . . 23 . The Lycopodium Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . 24 . Minor Alkaloids of Unknown Structure B Y R . H . F. MANSKE. . . . . .

...

Xlll

319 343 363 419 423 433 439 473 505

509

Contents of Volume VIII 1. 2. 3. 4. 5.

6. 7. 8. 9. 10. 11.

12. 13. 14. 15. 16. 17. 18. 19. 20 . 21 . 22 .

The Simple Bases BY J . E . SAXTON. . . . . . . . . . . . . . . . . Alkaloids of the Calabar Bean B Y E . COXWORTH . . . . . . . . . . . The Carboline Alkaloids B Y R . H . F. MANSKE . . . . . . . . . . . . The Quinazolinocarbolines B Y R . H . F. MANSKE . . . . . . . . . . . Alkaloids of Mirragyna and Ourouparia Species B Y J . E . SAXTON. . . . Alkaloids of Gelsemiurn Species B Y J . E . SAXTON. . . . . . . . . . . Alkaloids of Picralirna nitida B Y J . E . SAXTON . . . . . . . . . . . . Alkaloids of Alsronia Species B Y J . E . SAXTON . . . . . . . . . . . . The Iboga and Voacanga Alkaloids B Y W . I. TAYLOR . . . . . . . . . The Chemistry of the 2,2'-Indolylquinuclidine Alkaloids B Y W. I . TAYLOR The Pentaceras and the Eburnamine (Hunteria)-Vicamine Alkaloids BY . . . . . . . . . . . . . . . . . . . . . . . . . . W . I . TAYLOR The Vinca Alkaloids B Y W. I . TAYLOR. . . . . . . . . . . . . . . . Rauwolfia Alkaloids with Special Reference to the Chemistry of Reserpine B Y E . SCHLITTLER . . . . . . . . . . . . . . . . . . . . . . . . The Alkaloids of Aspidosperma. Diplorrhyncus. Kopsia. Ochrosia. Pleiocarpa. and Related Genera BY B . GILBERT . . . . . . . . . . . . . Alkaloids of Calabash Curare and Strychnos Species B Y A . R . BATTERSBY A N D H . F. HODSON . . . . . . . . . . . . . . . . . . . . . . . The Alkaloids of Calycanthaceae BY R . H . F. MANSKE. . . . . . . . . Srrychnos Alkaloids B Y G . F. SMITH . . . . . . . . . . . . . . . . . Alkaloids of Haplophyton cimicidum B Y J . E . SAXTON. . . . . . . . . The Alkaloids of Geissospermum Species B Y R . H . F. MANSKE AND W . ASHLEYHARRISON. . . . . . . . . . . . . . . . . . . . . . Alkaloids ofPseudocinchona and Yohimbe B Y R . H . F. MANSKE . . . . The Ergot Alkaloids B Y S. STOLLA N D A . HOFMANN . . . . . . . . . The Ajmaline-Sarpagine Alkaloids B Y W . I . TAYLOR. . . . . . . . . .

1 27 47 55

59 93 119 159 203 238 250 272 287 336 515 581 592 673 679 694 726 789

Contents of Volume IX 1 . The Aporphine Alkaloids B Y MAURICE SHAMMA. . . . . . . . . . . 2 . The Proroberberine Alkaloids R Y P. W . JEFFS . . . . . . . . . . . . . 3 . Phthalideisoquinoline Alkaloids B Y JAROSLAV STAN€K. . . . . . . . .

1 41 117

xiv

CONTENTS OF PREVIOUS V O L U M E S

CHAP TER 4 . Bisbenzylisoquinoline and Related Alkaloids by M. CURCUMELLIRODOSTAMO A N D MARSHALL KULKA . . . . . . . . . . . . . . . 5 . Lupine Alkaloids BY FERDINAND BOHLMANN A N D DIETER SCHUMANN 6 . Quinoline Alkaloids Other than Those of Cinchona B Y H . T. OPENSH.AW 7 . The Tropane Alkaloids B Y G . FODOR. . . . . . . . . . . . . . . . . 8 . Steroid Alkaloids: Alkaloids of Apocynaceae and Buxaceae B Y V. C E R NA ~N D F. SORM. . . . . . . . . . . . . . . . . . . . . . . 9 . The Steroid Alkaloids: The Salamandra Group B Y GERHARD HABERMEHL 10. Nuphur Alkaloids B Y J . T. WROBEL . . . . . . . . . . . . . . . . . 11. The Mesembrine Alkaloids B Y A . POPELAK A N D G . LETTENBAUER . . . 12. The Erythrina Alkaloids B Y RICHARD K . HILL . . . . . . . . . . . . 13 . Tylophora Alkaloids B Y T. R . GOVINDACHARI . . . . . . . . . . . . . 14. The Galbulimima Alkaloids B Y RITCHIEA N D W. C. TAYLOR. . . . . . IS. The Stemona Alkaloids B Y 0 . E . EDWARDS . . . . . . . . . . . . .

133 175 223 269 305 427 441 467 483 517 529 545

Contents of Volume X 1. Steroid Alkaloids: The Solanun Group BY KLAUSSCHRIEBER . . . . . . 2 . The Steroid Alkaloids: The Veratrum Group B Y S . MORRIS KUPCHAN A N D A R N O L D W . B.Y. . . . . . . . . . . . . . . . . . . . . . 3 . Erythrophleum Alkaloids BY ROBERT B. MORIN. . . . . . . . . . . . 4 . The Lycopodium Alkaloids BY D . B . MACLEAN. . . . . . . . . . . . 5 . Alkaloids of the Calabar Bean BY B. ROBINSON . . . . . . . . . . . . 6. The Benzylisoquinoline Alkaloids B Y VENANCIO DEULOFEU, JORGE COMIN,A N D MARCELO J . VERNENGO. . . . . . . . . . . . . . . 7 . The Cularine Alkaloids B Y R . H . F . MANSKE. . . . . . . . . . . . . 8. Papaveraceae Alkaloids B Y R. H . F. MANSKE. . . . . . . . . . . . . 9 . a-Naphthaphenanthridine Alkaloids BY R . H . F . MANSKE . . . . . . . 10. The Simple Indole Bases B Y J . E . SAXTON. . . . . . . . . . . . . . 11. Alkaloids of Picralima nitida B Y J . E . SAXTON . . . . . . . . . . . . 12. Alkaloids of Mitragyna and Ourouparia Species B Y J . E . SAXTON . . . . 13. Alkaloids Unclassified and of Unknown Structure B Y R . H . F . MANSKE . 14. The Tuxus Alkaloids B Y B. LYTHGOE . . . . . . . . . . . . . . . .

1

193 287 306 383 402 463 467 485 491 501 521 545 597

Contents of Volume XI 1. The Distribution of Indole Alkaloids in Plants

2. 3. 4. 5. 6. 7. 8. 9. 10.

B Y V. SNIECKUS . . . . . The Ajmaline-Sarpagine Alkaloids BY W. I. TAYLOR. . . . . . . . . . The 2.2‘-Indolylquinuclidine Alkaloids B Y W . I . TAYLOR. . . . . . . . The Zboga and Voacanga Alkaloids B Y W. I . TAYLOR. . . . . . . . . The Vinca Alkaloids B Y W. I . TAYLOR. . . . . . . . . . . . . . . . The Eburnamine-Vincamine Alkaloids BY W. I . TAYLOR. . . . . . . . Yohimbine and Related Alkaloids B Y H . J . MONTEIRO. . . . . . . . . Alkaloids of Calabash Curare and Srrychnos Species B Y A . R . BATTERSBY A N D H . F. HODSON . . . . . . . . . . . . . . . . . . . . . . . The Alkaloids of Aspidosperma. Ochrosia. Pleiocarpa. Melodinus. and Related Genera B Y B . GILBERT . . . . . . . . . . . . . . . . . . The Amaryllidaceae Alkaloids B Y W. C . WILDMAN. . . . . . . . . .

1 41 73 79

99 125 145 189 205 307

C O N T E N T S O F PREVIOUS VOLUMES

CHAPTER 1 1 . Colchicine and Related Compounds B Y W. C . WILDMAN A N D B. A. RJRSEY. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12. The F'yridine Alkaloids B Y W. A . AVERA N D T. E . HABCOOD. . . . . .

xv

407 459

Contents of Volume XZZ The Diterpene Alkaloids: General Introduction B Y S . W. PELLETIER AND L . H . KEITH . . . . . . . . . . . . . . . . . . . . . . . . . . 1 . Diterpene Alkaloids from Aconiturn. Delphinium. and Garrya Species: A N D L . H . KEITH . . The CIgDiterpene Alkaloids B Y S . W. PELLETIER 2. Diterpene Alkaloids from Aconitum. Delphinium. and Garrya Species: A N D L . H . KEITH . . The C2,,- Diterpene Alkaloids B Y S . W. PELLETIER 3 . Alkaloids of Alstonia Species B Y J . E . SAXTON . . . . . . . . . . . . 4 . Senecio Alkaloids B Y F R A N K L . WARREN. . . . . . . . . . . . . . . 5 . Papaveraceae Alkaloids B Y F . SANTAVY. . . . . . . . . . . . . . . 6 . Alkaloids Unclassified and of Unknown Structure B Y R . H . F. MANSKE . 7 . The Forensic Chemistry of Alkaloids B Y E . G . C . CLARKE. . . . . . .

xv

2 136 207 246 333 455 514

Contents of Volume XZI1 1 . The Morphine Alkaloids BY K . W. BENTLEY . . . . . . . . . . . . . 2 . The Spirobenzylisoquinoline Alkaloids B Y MAURICE SHAMMA . . . . . . 3 . The Ipecac Alkaloids B Y A . BROSSI.S . TEITEL.A N D G . V. PARRY . . . 4 . Alkaloids of the Calabar Bean B Y B . ROBINSON. . . . . . . . . . . . 5 . TheGalbulimima Alkaloids B Y E . RITCHIEA N D W. C . TAYLOR. . . . . 6. The Carbazole Alkaloids B Y R . S . KAPIL . . . . . . . . . . . . . . . 7 . Bisbenzylisoquinoline and Related Alkaloids B Y M . CURCUMELLI. . . . . . . . . . . . . . . . . . . . . . . . . . . RODOSTAMO 8 . The Tropane Alkaloids B Y G . FODOR . . . . . . . . . . . . . . . . . 9 . Alkaloids Unclassified and of Unknown Structure B Y R . H . F. MANSKE .

1 165 189 213 227 273

303 351 397

Contents of Volume XZV 1 . Steroid Alkaloids: The Veratrum and Buxus Groups B Y J . TOMKOA N D . VOTlCKf' . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 . Oxindole Alkaloids BY JASJITS. BINDRA . . . . . . . . . . . . . . . 3 . Alkaloids of Mitragyna and Related Genera BY J . E . SAXTON. . . . . . 4 . Alkaloids of Picralima and Alstonia Species B Y J . E . SAXTON . . . . . 5 . The Cinchona Alkaloids BY M . R . USKOKOVIC A N D G . GRETHE. . . . . 6 . The Oxaporphine Alkaloids B Y MAURICE S H A M MA A N D R. L . CASTENSON. . . . . . . . . . . . . . . . . . . . . . . . . . . 7 . Phenethylisoquinoline Alkaloids BY TETSUJIKAMETANI A N D MASUO KOIZUMI . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 . Elaeocarpus Alkaloids B Y S . R . JOHNSA N D J . A . LAMBERTON. . . . . 9 . The Lycopodium Alkaloids B Y D . B . MACLEAN. . . . . . . . . . . . 10. The Cancentrine Alkaloids B Y RUSSELL RODRIGO . . . . . . . . . . . 1 1 . The Securinega Alkaloids B Y V. SNIECKUS. . . . . . . . . . . . . . 12. Alkaloids Unclassified and of Unknown Structure B Y R . H . F. MANSKE .

1 83 123 157 181

225 265 325 347 407 425

507

xvi

CONTENTS OF P R E V I O U S VOLUMES

Contents of Volume XV CHAPTER 1. The Ergot Alkaloids B Y P. A. STADLER A N D P. STUTZ . . . . . , . . . 2. The Daphniphyllum Alkaloids B Y SHOSUKE YAMAMURA A N D YOSHIMASA HIRATA . . . . . . . . . . . . . . . . . . . . . . . . , . 3. The Amaryllidaceae Alkaloids B Y CLAUDIO FUCANTI . . , . . , . . . 4. The Cyclopeptide Alkaloids B Y R. TSCHESCHE A N D E. U. K A U B M A N. N. 5 . The Pharmacology and Toxicology of the Papaveraceae Alkaloids B Y V. FREININGER . . . . . . . . . . . . . . . . . . . . . . . , . . , 6. Alkaloids Unclassified and of Unknown Structure B Y R. H. F. MANSKE .

1 41 83 165

207 263

Contents of Volume XVI 1. 2. 3. 4. 5. 6.

7. 8. 9.

Plant Systematics and Alkaloids B Y DAVIDS. SIEGLER. . . . . . , . , The Tropane Alkaloids B Y ROBERTL. CLARKE . . . . . . . . . . . . Nuphar Alkaloids B Y JERZYT. WR6BEL . . . . . . . . . . . . . . . The Celestraceae Alkaloids B Y ROGERM. SMITH . . . . . . . . . . . The Bisbenzylisoquinoline Alkaloids-Occurrence, Structure, and Pharmacology BY M. P. CAVA,K. T. BUCK,A N D K. L. STUART. . . . . Synthesis of Bisbenzylisoquinoline Alkaloids B Y MAURICE SHAMMA A N D VASSILST. GEORGIEV, , . . . . . . . . . . . . , , . , , . The Hasubanan Alkaloids B Y YASUOINUBUSHI A N D TOSHIRO I B U K A. , The Monoterpene Alkaloids B Y GEOFFREY A. CORDELL . . . . . . . . Alkaloids Unclassified and of Unknown Structure B Y R. H. F. MANSKE .

1

83 181 215 249 319 393 43 1 511

Contents of Volume XVZI 1.

2. 3. 4. 5.

The Structure and Synthesis of C,,Diterpenoid Alkaloids B Y S. WILLIAM PELLETIER A N D NARESH V. MODY . . . . . . . . , Quinoline Alkaloids Related to Anthranilic Acid BY M. F. GRUNDON , . The Aspidospmrna Alkaloids BY GEOFFREY A. CORDELL. . . . . . . , Papaveraceae Alkaloids, I1 B Y F. S A N T ~ V. ) . . . . . . . . . . . . . Monoterpene Alkaloid Glycosides B Y R. S. KAPILA N D R. T. BROWN . ,

1

105 199 385 545

-CHAPTER

1-

ER YTHRINA AND RELATED ALKALOIDS S. F. DYKE*AND S. N. QUESSY~ School o/Chei?iisfry.The Uniuersitj. of Bath. Bath, A t o i l , Encqland

I. Introduction . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . , , . . . . . . . . . . , , , . . . . . , 11. Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Occurrence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................... B. Isolation and Detection . . . . . . . . . . . . . . . . C. Structure Determination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Homoerythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Occurrence and Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Nomenclature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Structure Determination . . . . . . . . . . . . . , . . . . . . . . . . , . . . . . . . . IV. Cephalotasus Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Occurrence and Isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Structure Determination . . . . . . ...... . .. ... . .. V. Biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Erythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Homoerythrina Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Cephalotasus Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . , , . . . . . . . . , . VI. ..... ...... ..... .. ..... . ..... .............................................. B. Homoerythrina Alkaloids . . . . _ . _ . . _ . . ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. Cephalotasus Alkaloids . . . . . . . . .............. ............. V11. Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

2 2 6

1 21 21 30 31 42 42 45 51 51 58 59 61 61 12 16 91 93

1. Introduction The last review in this series (1)covered the literature to the end of October, 1966. At that time 10 Erythrina alkaloids were known, and the structures and stereochemistries of most of them had been established. The total synthesis of erysotrine had been described by Mondon’s group in a preliminary communication (2),but nothing was known about the biosynthesis of these alkaloids, although some speculations had been reported. * Present address: Department of Chemistry. Queensland Institute of Technology, Brisbane. Queensland, Australia. ’ CSIRO postdoctoral fellow, 1979. Present addrcss: Research and Dcvclopment Department. Riker Laboratories, Thornleigh, New South Wales, Australia. THE ALKALOIDS. VOL. X V l l l Copyright @ I Y 8 1 by Academic Press. Inc. All rights of reproduction an any rorin reserved.

ISBN 0-12-469SlR-3

2

S . F. DYKE AND S. N. QUESSY

Frc;. 1. The structures and accepted numbering system for A : 1,6-diene skeleton and B : A1(6)-alkene skeleton.

In the intervening 13 years the subject has expanded dramatically; over 60 compounds are now classified as Erythrina alkaloids, and the structures of most of these have been deduced from a combination of mass spectral fragmentation analysis, H-NMR spectral interpretations, and chemical correlations with alkaloids of known structures. Some ‘‘unusual’’ alkaloids have been obtained from certain Cocculus species and a new, as yet small, subgroup, the Homoerythrina alkaloids, has been recognized. The biosynthetic pathway from tyrosine through the aromatic bases to the erythroidines has been elucidated, and some significant advances have been made in methods of total synthesis. Reviews of the Erythrina alkaloids since 1966 have appeared (3-6). Because of the postulated biosynthetic derivation of the Cephalotaxus alkaloids from the Homoerythrina bases, the former, relatively new group is included in this chapter. Anticancer activity has been found in certain members of the Cephalotaxus group, so the subject has already been reviewed several times (7-9). Annual coverage is given to the Erythrina, Homoerythrina, and Cephalotaxus alkaloids in the Specialist Periodical Reports of the Chemical Society (20-ZZa). The Erythrina alkaloids are conveniently divided into two main structural groups: the 1,6-diene group and the A1(6)-alkene group (see Fig. 1). The biogenetically important alkaloid erysodienone cannot be classified in this way. The present chapter covers the literature from November 1966 to the end of May 1979. 11. Evythvitza Alkaloids

A. OCCURRENCE There are now over 60 Erythrina alkaloids of known structure 1-61 (see Figs. 2-4) and several more, the structures of which are yet to bz assigned (12). The alkaloids occur in species of Erythrina (Leguminosae), a genus of wide distribution in tropical parts of the world, and in species of Cocculus

R'

1

2 3 4 5 6 7 8 9 10

11 12 13 14 1s* 16 17*

Erysotrine Erysotramidine Erythravine Erythraline Erysovine Erysoline Erysodine Erysonine Erysopine Erysothiovine Glucoerysodine Eryso thiopine Erysophorine Coccuvinine Coccolinine Coccuvine Coccoline

CH30 CH,O CH30 -OCH2CH30 CH,O HO HO HO CH30 h U

CH30 H H H H

R2

R3

X

2H 0 2H 2H 2H 2H 2H 2H 2H 2H 2H 2H 2H 2H 0 0 0

FIG.2. Erj,llrrina alkaloids: 1,6-diene series. a : H0,CCH2S0,-,

R' 18 19 20 21 22 23 24 25 26 27 28 29 30 31

Erythrartine Erythristemine Erythrascine Erythrinine 1 I -Methoxyerythraline 1 I-Oxoerythraline I I-Hydroxyerysovine I I-Methoxyerysovine 1 I-Oxoerysovine 1 I-Hydroxyerysodine 1 I-Methoxyerysodine 1 I-Oxoerysodine I I-Methuxyerysopine 1 1-0xoerysopine

CH, CH, CH 3

R2

R3

CH3 CH 3 CH,

OH OCH OAc OH OCH -0 OH OCH, -0 OH OCH, -0

-CH,-~-CH, CH, ~~

CH, CH, CH, H H H H H

H H H CH.3 CH 3 CH, H H

,

0ch3 -0

b : I-/~-glucosyl,c: hypaphorine ester, d : alkaloid is possible artifact.

R1orJp

4

S. F. DYKE AND S. N. QUESSY

-

RZO

" ' oR

CH,O"

CH,O' R'

32" 33" 34* 35*

Erythrabine Crystamidine 10,ll-Dehydroerysovine 10,ll-Dehydroerysodine

R2

X

36 Isococculidine R

CH, CH, -CH2CH, H H CH,

0 0 2H 2H

37 Isococculine R = H

* means an alkaloid is a possible artifact.

X R' 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54

Dihydroerysotrine Erythratidine Erythratidinone Erythramine Erythratine Erythratinone Dihydroerysovine Erysosalvine Erysosalvinone Dihydroerysodine Erysotine Eryso tinone Erysopitine Erysoflorinone Coccutrine Erythroculine Cocculidine

H H H H H H H H H H H H H H CH,O H H

R2

R3

CH,O CH,O CH,O CH,O CH,O CH,O -OCH,O-OCH20-OCH,OCH,O HO CH,O HO CH,O HO HO CH,O HO CH,O HO CH,O HO HO HO HO H OH CH,O CH,O,C H CH ,O

FIG.3 . Erythrinu alkaloids: Al(6) alkene series.

X H OH =O H OH =O H OH =O H OH =O OH =O H H H

= CH,

1.

E R Y T H R I N A AND RELATED ALKALOIDS

5

CH,O

CH 3

0

0

0

57 3-Demethoxyerythratidinone

59 r-Erythroidine

58 Erysodienone

60 [I-Erythroidine

61 Cocculolidine

FIG.4. Erythrina alkaloids: miscellaneous

(Menispermaceae), a genus of more limited distribution in tropical areas (13). A conspectus of the genus Erythrina was published by Krukoff who listed 108 species and 9 hybrids (14), and over half of these have been examined for their alkaloidal content. Attention must be drawn to the fact that Krukoff has reclassified several species. Notably, E. lithosperma has been subdivided such that E. lithosperma Blume is now a synonym for E. variegata L., wherer.5 E. lithosperma Miguel is a synonym for E. subumbrans Merril. In addition, E. orientalis, E. variegata uar. orientalis, and E. indica are synonyms for E. variegata L. (14).This reclassification has resulted in some misleading claims and doubtful identifications in the literature (15). Most studies have concentrated on examination of the seeds, which typically contain 0.1% alkaloids, although alkaloids have been isolated from the leaves, stalks, stems, bark, roots, pods, and flowers of Erythrina species. An extensive survey of Erythrina species has been made by two groups using combined GC-MS; Rinehart and co-workers at Illinois have examined American species (15, 16) and Jackson and co-workers at Cardiff examined old world species (12, 17). Other major investigations have been carried out by Barton and co-workers (18-21), by Ito and co-workers in Japan (22-32), and by Ghosal and co-workers (33-37), and Singh and Chawla in India (38-41). From the results of these studies it is apparent that individual species are often distinctive in their alkaloid profile, although the sections and subgenera are not clearly marked. Several patterns do emerge, however. Erysovine (5)and erysodine (7) are ubiquitous, although

6


they do not occur in all parts of each plant (12, 15-17); the sections Breviflora and Edules are low in alkaloid but high in amino acid content (13,42); the major alkaloids of E. folkersii are of the 1,6-diene type whereas those of E. salvizjlora are of the l(6)-alkene type ( 1 5 ) ; the American species do not contain 1 1-oxygenated alkaloids and presumably lack the capacity to hydroxylate ring C (12, 21). However, Ito has reported the isolation of erythrinine (21) from E. crysta galli L., an American species (30). The hybrid species E. x bidwillii elaborated two new alkaloids, erythrinine (21) (24, 25) and the dibenzo[e,f]azonine base erybidine (62), (23, 26) which had not been found in the parent species E. crysta galli and E. herbacea (13). Erythrinine has since been isolated from E. crysta galli (30) and erybidine has been isolated from several other Erythrina species (12, 27, 30,31). Although the alkaloidal profile of Erythrina species is often characteristic, there is considerable quantitative variation in different samples (17). Differences have been noted in the content of the bark, seed, and leaves of the plant (33, 35, 43, 4 4 , and some striking variations have been reported. In their GC-MS examination of E. folkersii, Rinehart’s group (15) failed to detect erythraline (4),which had been reported in an earlier study of this plant (45),although 4 could be detected in other species (16).Ghosal et al. reported erysotrine (1) to be the major component by far in the bark of E. variegata var. orientalis, with only minor amounts of 5 present (33), whereas Singh et al. (41) in a more recent investigation reported only 5 from the bark of the same species. Whereas some of the variation may result from the location of the plant or its age at harvest, there is some evidence for chemical variants within species. Barton et al. (21)reported a thorned variety of E. lithosperma Blume (E. variegata L.) that contained only erysotrine and a smooth variety that contained 1 along with erythratidinone (40), 3-demethoxyerythratidinone (57), and traces of erythraline (4).Letcher referred to two varieties of E. lysistemon harvested in Southern Rhodesia which contained either 1 or 1 1-methoxyerythraline (22) but not both. Although erythristemine (19) had been isolated from E. lystistemon from South Africa none was found in the varieties from Southern Rhodesia, and no change in the nonpolar alkaloids present in the leaves could be detected over a period of four months. It was therefore suggested that there are at least three chemical variants of E. lysistemon (46). B. ISOLATION AND DETECTION

The procedure of Folkers, where the ground plant material is extracted with hexane to remove fats, is widely used; but Rinehart and co-workers (16) pointed out that a significant quantity of alkaloid could be detected

1.

ERYTHRI.VA AND RELATED ALKALOIDS

7

by GC-MS analysis of the hexane fraction, so that earlier examinations where this fraction was discarded must be regarded as incomplete. Alcoholic extraction of the remaining marc gave the “free” alkaloids, whereas acid hydrolysis gave rise to the liberated alkaloids (usually the largest fraction). Ghosal(35) has described a detailed flow chart for the isolation of a variety of alkaloids from E. variegata. The greatest advance in the isolation and identification of Erythrina alkaloids has come from the powerful combination of GC-MS, which has provided a methodology for comprehensive taxonomic investigation of the whole genus. Its value derives from the facile identification of the alkaloids from their fragmentation patterns, the speed and accuracy of the method, the avoidance of large-scale extraction and chromatography, and the requirement of only milligram quantities of crude alkaloid extract. The power of the technique has been demonstrated by the number of new alkaloids detected and the number of species investigated using it (12, 15, 16). There are rarely more than eight alkaloids present in a species, and the possibility of the same GC retention time is not normally a problem. In cases where overlap has been observed it has proved possible to identify both components from the mass spectrum of the mixture. The crude alkaloid extracts are treated with trimethylsilyldiethylamine to form volatile TMS derivatives of the hydroxylated components. The presence of a free phenolic or hydroxyl group is then detected by an ion with mje 73 [(CH,),Si+]. Positional isomers [e.g., erysovine (5) and erysodine (7)] are resolved although u- and 8-erythroidine are not. The presence of perythroidine (60) can be estimated since it shows some enol content under the silylation conditions and gives rise to a monotrimisyl derivative with m/e 345 (15). As a supplement to electron impact MS, field ionization MS, which allows identification of the alkaloids by their molecular formula, has been introduced (47). The combination of HPLC-field desorption MS, which utilizes the greater resolving power of HPLC over GC, has been applied; and the presence of alkaloids not detected by GC-MS was revealed in one case (12). Various other alkaloids have been found concurrently with the Erythrina group. Hypaphorine is by far the most common, but choline, N-nororientaline, and erybidine (62) are not uncommon.

DETERMINATION C. STRUCTURE I . X-Ray Crystal Structures and Absolute Stereochemistry The absolute stereochemistry of the aromatic Erythrina alkaloids has been determined. An X-ray analysis of the 2-bromo-4,6-dinitrophenolate

8


salt of erythristemine confirmed the assumption that the 3R,5S configuration of the erythroidines exists in the aromatic group. This result also confirms the common biosynthetic origin of the two types. The configuration of the methoxyl group at C-11 was found to be S. The use of 2-bromo4,6-dinitrophenol for the preparation of a heavy-atom derivative was novel and may be applicable in other cases (20,48). The absolute stereochemistry of the A1(6)-alkene alkaloids cocculine (56) and coccutrine (52) has also been established by X-ray analysis. It was found that the cyclohexene ring A exists preferentially in an approximate half-chair conformation in the free base, but this was altered to an envelope conformation on protonation of the nitrogen atom (49). R I

CH,O'19 Erythristemine

56 R = H Cocculine 52 R = CH,O Coccutrine

The crystal structures of the alkaloids containing a hydroxyl group at C-2 have not been determined. The stereochemistry of erythratine (42) was established as 2R,3R,5S by Barton et al. (19) and that of erythratidine (39) as 2S,3R,5S by the same group (21)on the basis of optical rotation and N MR data for both pairs of C-2 epimers (see Section II,C,4b). The configuration at C-2 for erysosalvine (45), erysotine (48), and erysopitine (50) has not been defined. The absolute stereochemistry of other alkaloids rests on comparison of their CD and NMR characteristics with those of alkaloids of known stereochemistry as well as on chemical interconversions. 2. Spectral Characteristics a. Infrared and UV Spectra. The 1,6-diene alkaloids show IR absorbances a t 1610 cm-' and UV absorbances around 285 (dioxygenated aromatic ring) and 230-235 nm (diene). The 8-0~0-1,6-dienegroup exhibits a lactam absorbance at 1665 cm-' and an additional UV absorbance at 256 nm arising from the dienone chromophore (21). The Al(6)-alkene group absorb in the UV around 225 nm, whereas the enone group usually shows UV absorbance around 230 nm and IR absorbance in the region of 1675-1698 cm-'. Erysodienone (58) exhibits UV

1.

E R Y ? . H R / N A AND RELATED ALKALOIDS

9

absorbances at 240-242 and 285nm and IR bands at 1672, 1655, and 1614 cm-' (34). b. Circular Dichroism. The 1,6-diene alkaloids exhibit strong positive Cotton effects and previous attempts to relate this to the absolute configuration, using diene rules, have led to assignments of configuration opposite to that found by X-ray analysis. An explanation for the failure of the diene rules for Erythrina and other systems has been advanced. The allylic methoxyl system (at C-3) has helical chirality opposite to that of the diene chromophore, and it appears that the sign of the diene Cotton effect is determined by the former group (50). Members of the A1(6)-alkene group also show a positive Cotton effect, and this was used to assign the absolute configuration of cocculine (56) and cocculidine (54), later supported by X-ray analysis (51, 52). c. Mass Spectrometric Characteristics. Because of the heavy reliance on MS identification of Erythrina alkaloids, several studies of their fragmentation patterns have been made. A comprehensive analysis of the fragmentations of erythrinanes was described by Migron and Bergmann (53)but is not discussed here. The MS of a variety of Erythrina alkaloids were studied by Boar and Widdowson (54) who proposed fragmentation schemes based on the usual techniques of accurate mass measurement of major ions and on metastable analysis. Further elaboration was made through the use of deuterium-labeled samples. Only the general MS features will be discussed here, as several detailed schemes can be found in the literature (15, 21, 54). All the 1,6-diene structures show a simple fragmentation pattern, summarized in Scheme 1. The main pathway involves loss of the allylic substituent at C-3 which allows distinction between the isomeric groups. For example, erythravine (3) can be distinguished from erysovine (5) and erysodine (7) by the nature of RO. However, distinction between pairs isomeric in ring D, that is, between 5 and 7 or between 6 and 8, cannot be made by MS alone.

+ m 2m~ ~ .c trj CY l+.

IcJn71+. RO

SCHEME I . Mujor

RO

M S ~ f r a g i ~ ~ c ~ t ~ tpatterii u t i o r i fhr

1.h-drene srries (R = H,CH, or TMS)

The A1(6)-alkene alkaloids show a more complex fragmentation pattern in which loss of the allylic substituent is of only minor importance. A major

10


fragmentation pathway involves a retro-Diels-Alder reaction (path a in Scheme 2), and an alternative pathway involves loss of the C-2-C-3 unit (path b in Scheme 2). Each ion subsequently loses a hydrogen atom. The nature of the substituent at C-3 is readily established from path a and for all known Al(6)-alkene types is methoxyl. The substituent at C-2 is then defined by M + -C3H,0R, where R is usually H or OH (15, 16, 54). Distinction between A1(6)-alkene types and the isomeric A2( I)-alkene types [e.g., isococculine (37)] can be made by MS. For example, 37 exhibits a fragmentation pattern similar to the l ,6-diene types.

/ -C,I!,O

q7’+

\b -C,H ,OR\

//

HC SCHEME 2. Mujor M S Jkugmentutionpatiern for A1(6)-aNceneseries (R = H or OH)

The enone alkaloids, such as erythratidinone (40), do not undergo fragmentation by path b in Scheme 2, but exhibit loss of CO as shown in Scheme 3 (21, 54). Alkaloids containing 1 I-hydroxyl or 11-methoxyl groups show additional ions arising from loss of H,O or CH30H, respectively, from the

C * , O V

C

0

I1

0

CHO SCHEME

3. Frugmenmthn puirern .for enone f?‘pes

1.

ER YTHRIiVA A N D RELATED ALKALOIDS

11

parent ion (12, 20, 22, 46). The 1 1-oxoalkaloids show a characteristic fragmentation ion resulting from cleavage at ring C. For example, the TMS derivative of 11-oxoerysodine (29) exhibits a characteristic ion with m/e 222 (12)(see Scheme 4).

SCHEME 4

d. NMR Characteristics. Once the erythrinane skeleton is established, it is possible to deduce the complete structure from detailed NMR data with the aid of decoupling, NOE, and INDOR techniques. Assignments of stereochemistry at C-2, C-3, and C-11 have been made from the values of coupling constants by comparison with data from related alkaloids in the group, for which crystal structures have been determined (19-21,43,55-58). In a review of the NMR of the alkaloids (59) coverage is given to the Erythrina group. Protons attached to C-14 and C-17 in the aromatic ring can be readily distinguished. Irradiation in the benzylic region causes a sharpening in the signal due to H-17 (19),whereas irradiation of the axial C-3 proton produces about 15% NOE for the signal due to H-14 (57). The NOE effect arises because H-14 lies over ring A and spatially near the axial C-3 proton. The INDOR technique can also be used to locate H-14 (58). Combinations of these techniques have been used to determine the position of substituents in the aromatic ring (43,56-58). For example, dihydroerysovine (44)was found to contain methoxyl and hydroxyl groups at C-15 and C-16, and their relative positions were determined by NMR. The resonance for the proton at C-14 (6 6.99) was located by INDOR and confirmed by NOE. When the other aromatic proton (6 6.30) was monitored a NOE and decoupling effect was observed at the aromatic methoxyl signal (6 3.27), but this effect was not observed when the C-14 proton was monitored. This established that the methoxyl group was near C-17, i.e., at C-16 (57). The usefulness of the technique has also been demonstrated with cocculidine (54), which is of firmly established structure (60).The position of the aromatic methoxyl group could be established using INDOR by monitoring each aromatic proton in turn. It was found that the aromatic proton (6 6.93) with J value of 2.5 Hz was spatially near the C-3 axial proton,

12


hence the methoxyl group was at C- 15 (58).This was supported by synthesis of the alternative C-16 methoxyl isomer (63) and comparison of its NMR spectrum using INDOR and NOE techniques (58).

HO

44 Dihydroerysovine

54 R' 63 R'

= =

H , R Z = CH,O Cocculidine CH,O, RZ = H

The stereochemistry at C-3 in the 1,6-diene series can be determined from the value of J 2 , 3 . In all cases this value is small, about 2 Hz, suggesting that the proton at C-3 is quasi-axial and hence that the methoxyl group is equatorial. This assignment is supported by the observation of diaxial couplings (J3ax,4ax z 10 Hz) between protons at C-3 and C-4 (19-21,55, 56). The stereochemistries at C-2 and C-3 in erythratine (42) and erythratidine (39) were established partly by NMR (19, 21). With the aid of INDOR the value of J3,4was found to be 5.5 and 12 Hz for both alkaloids, suggesting that the C-3 proton was axial in both cases, This was supported by interconversion studies (see Section II,C,4b). In erythratine (42) the value of was found to be 7.5 Hz and in its C-2 epimer 3-4 Hz. This suggested stereochemistries A and B, respectively (as shown in Fig. 5), for erythratine and its C-2 epimer. The values off,,, (4.25 Hz) and 52,3(4.25 Hz) in erythratidine (39) suggested that the proton at C-2 is equatorial and that the stereochemistry is that of B in Fig. 5. Thus, 42 and 39 have opposite stereochemistry at C-2. The position of the extra methoxyl group in erythristemine (19) was established at C-11 when it was found that irradiation of the proton at C-17 caused slight narrowing of the methine signal at 6 3.94. The shift of this

OH A

B

FIG.5 . Stereochemistries in ring A

1.

ER YTH-HRINA A N D RELATED ALKALOIDS

13

methine suggested an attached methoxyl group, thus identifying the methoxyl group at C-l 1. This was confirmed by X-ray analysis, which also gave the absolute configuration. The value of J,,,, (4 Hz) was found with the aid of INDOR since the methoxyl signals partly obscured the methine signal. The stereochemistry at C-1 1 in the other 11-oxygenated alkaloids have been related to erythristemine by comparison of the value J,,,,,, which all lie around 4 Hz, suggesting the same configuration at C- 11 (43).

,

3. 1,6-Diene Series

a. Simple Types. Resolution of the final ambiguities in the structures of erysodine (7), erysovine (5), and erysonine (8) was discussed in the previous review (1)of this treatise on the basis of a preliminary communication (18). The complete details of this work have now been published (19). Erysotrine (l),long known only as a synthetic product, was isolated from E. suberosa Roxb. in 1969 (38,39) and has since been identified in a large number of Erythrina species (12, 16, 17, 31, 33, 44). An investigation of E. folkersii by Krukoff and Moldenke by GC-MS (15) revealed the existence of two new 1,6-diene alkaloids erythravine (C,,H,,NO,) and erysoline (C,,H,,NO,). Erythravine was identified as 3-desmethylerysotrine (3) from its MS fragmentation pattern. Erysoline appeared to bear a similar relationship to either 5 or 7. Demethylation of samples of both 5 and 7 resulted in the identification of erysoline with 3-desmethylerysovine (6) (see Scheme 5), from GC retention time and spectroscopic comparisons. R'O

R20

CH,O"

5 R' 7 R'

= CH,, = H,

R2 = H Erysovine

R Z = CH, Erysodine

HO' 6 R' 8 R'

= CH,, = H,

R2 = H Erysoline R 2 = CH, Erysonine

SCHEME 5

Erysophorine (13)was isolated from the water-soluble extract of the seeds of E. arborescens Roxb. (37). The molecular formula C,,H,8N,0,C1 was established by analysis. The mass spectrum of 13 gave no molecular ion but exhibited fragments consistent with a 1,6-diene Erythrina alkaloid and a carboxylated indole-3-alkylamine. Erysophorine appeared to be a combined alkaloid, and its UV spectrum was similar to that of an equimolar mixture

14


13 R = Hypaphorine

64 Hypaphorine

of 5 and hypaphorine (64). The presence of three quaternary N-methyl groups and two methoxyl groups was evident from the NMR spectrum. Hydrolysis of 13 in dilute hydrochloric acid proceeded readily affording 5 and 64, and erysophorine was deduced to be erysovine linked by esterification at C-15 to hypaphorine. This was the first example of a phenolic Erytkrinu alkaloid esterified to an acid other than sulfoacetic or hexuronic acids. Recently, another combined alkaloid has been isolated, this time from the seeds of E. oariegata L. (43).Hydrolysis of the alkaloid yielded 7 ; and since 64 was also positively identified in the extracts, it is possible that this alkaloid could be the complementary positional isomer of erysophorine. b. 8-0x0Types. Ito's group isolated two new alkaloids, erythrabine (C,,H,,NO,) (32)and erysotramidine (C,,HzlNO4) (2), from E. arborescens Roxb., which were both of higher oxidation level than the 1,6-diene types (27,28).The structures were assigned on the basis of spectroscopic and chemical investigations. Later, a similar alkaloid, crystamidine (C, *HI,NO,), was isolated from E. crysta galli L.; and MS data indicated an alkaloid of the 1,6-diene type. The NMR spectroscopic data established the presence of a methylenedioxy group, a methoxyl group, and two para-oriented aromatic protons. The UV and IR data suggested a heteroannular conjugated system, and the carbonyl group ( v ,,,1695 cm-I) was placed at C-8 after detailed examination of the NMR spectrum. The structure of crystamidine (33)was proved by correlation with erythraline (4), (see Scheme 6). Catalytic reduction of 33 gave a product (65) identical to that obtained by oxidation

33 Crqstdmidinr

65

SCHEME 6

4 Erjthralme

1.

E R Y T H R I N A A N D RELATED ALKALOIDS

15

of 4 with potassium permanganate, followed by catalytic reduction (32).This also established the stereochemistry at C-5 and C-3 in crystamidine. Two other 8-0x0 derivatives [coccoline (17) and coccolinine (15)] have been isolated from Cocculus species, and these are discussed separately later (see Section 11,C,5). It has been recognized that, since oxidation at C-8 is relatively facile, the 8-0x0 derivatives are probably artifacts produced in the drying process (55). Both 10,ll-dehydroerysovine (34) and 10,lldehydroerysodine (35), which have been detected in GC-MS studies, are thought to be artifacts produced by an elimination reaction from 11-methoxyor 11-hydroxyalkaloids (12).

c. C-11 Oxygenated Types. The first Erythrina alkaloid with oxygenation at C-11 was isolated from E. lysistemon Hutchinson and given the name erythristemine (20). The molecular formula C,oH25N04was established by analysis and confirmed by high resolution MS. The IR spectrum showed no hydroxyl nor carbonyl absorbances and the UV spectrum was almost identical to that of erythraline 4. The MS data were consistent with a 1,6-diene structure containing an additional methoxyl group in ring C or D. Careful examination of the NMR spectrum with the aid of INDOR (see Section II,C,2d) suggested that the methoxyl group was at C-11. Structure 19 was proposed and confirmed by X-ray analysis of the 2-bromo-4,6dinitrophenolate salt (20,48),which also established the complete stereochemistry shown in structure 19.

19 Erythristemine

A little later 11-methoxyerythraline (22), isolated as a pale yellow gum, was obtained from the same species (46).The spectroscopic properties of 22 were similar to those of erythristemine except that a methylenedioxy group was present instead of the two aromatic methoxyl groups in 19. The NMR spectrum of 22 could be interpreted completely without the necessity of INDOR, as the signals did not obscure one another. The coupling data were consistent with H-3 being quasi-axial, as in 19. At about the same time, Ito et al. (22) reported the isolation of an alkaloid C,,HIgNO4 from E. indica Lam. (now classified as E. variegata L.) to which

16


they gave the name erythrinine. The IR spectrum showed a hydroxyl function, which was further demonstrated by the preparation of an 0-acetate, and the UV and MS data suggested a 1,6-diene structure. Catalytic reduction of erythrinine followed by hydrogenolysis over Palladium black in aqueous hydrobromic acid gave tetrahydroerythraline (66) (see Scheme 7). This established the basic structure and the stereochemistry at C-5 and C-3. The hydroxyl group was placed at C-1 1 because of the ease of hydrogenolysis, and since oxidation gave a ketone in conjugation with the aromatic ring (vmaX1680 cm- I ) . Therefore, structure 21 was established for erythrinine although the configuration at C-1 1 was not determined. Erythrinine has since been isolated from E. x bidwillii (24, 25), E. crysta galli (30, 32), Eryrhrina species from Singapore (31),and old world species (12). OH (iJPtO,-H,

(ii) P d ~H , HBr ,

21 Erythrinine

66 Tetrahydroerythraline

SCHEME I

The name erythrinine had been assigned to an alkaloid isolated in 1969 from E. lithosperma (61). The formula for this alkaloid was found to be C30H,,N,0,, and little structural information was known except that it contained four methoxyl groups and one amide function and that all four nitrogen atoms were present in rings. No further elaboration of the structure has been reported. Erythrascine (C,,H,,NO,) was isolated from the seeds of E. arborescens Roxb. collected in India (36).The MS fragmentation pattern was typical of a 1,6-diene type, and the IR spectrum exhibited an absorbance at 1728 cmwith no hydroxyl absorption. The MS and NMR spectroscopic data were consistent with erythrascine being 11-acetoxyerysotrine (20). Soon afterwards the Japanese group reported the isolation of 1 I-hydroxyerysotrine (CI9Hz3NO,)from the seeds of the same species (27). Structure 18 was established from spectroscopic and chemical correlation studies. It is not clear whether both alkaloids 18 and 20 are natural products, since the possibility that erythrascine was an artifact was not discussed and since no other 11-acetoxyalkaloids have been reported. Further studies by Ito and co-workers (31) have resulted in the isolation of erythrinine (21) and 11hydroxyerysotrine (18) from other Erythrina species. Recently, examination

1.

E K Y T H R I . Y A A N D RELATED ALKALOIDS

17

CH,O’ 20 R 18 R

= CH,CO Erythrascine = H ll-Hyroxyerysotrine

(erythrartine)

of the flowers of E. uariegata L. collected in Egypt resulted in the isolation of an alkaloid (CI9H,,NO,) to which the name erythrartine was given. Erythrartine was deduced to be 1l-hydroxyerysotrine (18) on spectroscopic evidence (43).The authors were unable to compare their sample with that reported by the Japanese group. The statement that 18 is the first example of an ll-oxygenated Erythrina alkaloid from E. variegata (43) is incorrect since erythrinine (21) was isolated by Ito et al. in 1970 from E. indica Lam (22),a synonym for E. variegata L. (14). It has been suggested (43) that the absolute configurations of the 11oxyerythrina alkaloids 18, 20, 21, and 22 are the same as that of erythristemine (19), that is llj? (or 1lS), on the basis of correlation of optical rotations and since the value of J,,,,, is the same. Examination of old world Erytlzrina species by GC-MS has revealed the existence of a larger variety of 1 1-oxygenated alkaloids 23-31 (see Fig. 2), including examples with 1I-0x0 functions. The assignment of the structures of these compounds rests entirely on MS evidence (12)(see Section II,C,2c). 4. A1(6)-Alkene Series a. Without C-2 Oxygenation. Dihydroerysovine (44) and dihydroerysodine (47) have been isolated from Cocculus species (see Section II,C,5), although dihydroerysotrine (38) is still known only as a reduction product of erysotrine (1). Erythramine (47), previously known as a reduction product of erythraline (4) (62).was detected in E. crysta galli and in E. glauca Willd. (now classified as E. fusca Loureiro) (19). Since there was insufficient sample isolated, erythramine was prepared from erythraline and its structure established by NMR. In addition, erythramine was prepared by an alternative route from erythratine (42) (see Scheme 8) by chlorination and reduction. Since 42 could also be converted to erythraline (19),an alkaloid of known stereochemistry (631, the position of the double bond as well as the configurations a t C-3 and C-5 in erythramine were firmly established.

18


42 Erythratine

41 Erythramine SCHEME 8

Several other alkaloids like 41 but with abnormal substitution pattern in ring D, have been isolated from Cocculus species and are discussed in Section II,C,5. b. With C-2 Oxygenation. Erythratinone (43), which was synthesised by oxidation of 42 (19), has been isolated by Barton et al. (19) as a major alkaloid in E. crysta galli. Further work by the same group has resulted in the isolation of a similar alkaloid erythratidinone (C, 9H23N04)from E. lithosperma Blume (now classified as E. variegata L.) (21). This alkaloid exhibited spectroscopic data similar to those,of 43 and erythratidinone was established as a 1(6)-en-2-one structure. The NMR data established the presence of three methoxyl groups and the dpbstitution pattern of ring D. With the aid of INDOR it was concluded that the proton at C-3 was axial from coupling values of 5.5 Hz with H-4e, and 12.0 Hz with H-4a. Structure 40 was proposed for erythratidinone since borohydride reduction (see 273-) and its C-2 Scheme 9) gave the known erythratidine (39, [a],, 142"). Erythratidine had been isolated earlier from E.Jufcata epimer ([.ID Bentham (64),but its stereochemistry was unknown. By application of Mills' rule (65)39 was assigned the 2 s configuration (as 39), which was opposite to that established for erythratine (42)by the same group (19). Further evidence

+

+

0 40 Ervthratidinone

OH

39 Erqthratidine ( + C-2 epimer)

SCHEME 9

1 Erysotrine

1.

ERYTHRINA AND RELATED ALKALOIDS

19

for the configuration at C-2 in 39 came through the analysis of its NMR spectrum (see Section II,C,2d). The absolute configuration at C-5 in both 39 and 40 was established by dehydration of 39 to give erysotrine (1) (see Scheme 9) along with 2-chlorodihydroerysotrine. A second enone alkaloid (CI8H,,NO,) was isolated from E. lithospernza Blume in the same study and identified as 3-desmethoxyerythratidinone (57) by the similarity of its spectroscopic properties to those of erythratidinone (40). In the first GC-MS examination of Erythrina species, several new A1 (6)alkene-type alkaloids were discovered in E. salvi$ora Krukoff and Barneby (15). Erysotinone (49), previously known only as a synthetic racemate (66), was identified from its MS fragmentation pattern. The substitution pattern in ring D was established by conversion of the isolated alkaloid to dihydroerysodine (47)which was prepared from a sample of erysodine (7)(see Scheme 10). Another G C fraction which gave an identical MS to that of 49 was assigned the isomeric structure 46 and given the name erysosalvinone. A further fraction exhibiting a n enone fragmentation pattern similar to both 46 and 49 but with a molecular ion at 58 amu higher, due to an extra TMS (67) and one fewer CH, (15) group, was assigned structure 51 and named erysoflorinone. Fractions with MS fragmentation patterns similar to that of erythratidine were isolated and one identified with the reduction product of erysotinone (49). This product 48 was previously prepared from 49 by Barton et al. (68) and given the name erysotine, but neither erysotine (48) nor erysotinone (49) had been previously obtained from natural sources. Erysotine was found to have an N M R spectrum similar to that of erythratidine (39),and methylation of 48 using diazomethane gave a product that had identical melting point and G C retention time to that of 39 (see Scheme 11). In view of the fact that the structure given by Millington et al. (15) was that of 2-epierythratidine rather than 39, their stereochemistry for erysotine was also incorrect. This would seem to suggest that erysotine, like erythratidine, has the 2 s configuration; however the structures given by Millington et al. for both erysotine and erythratidine (Fig. 6 in ref. 1 5 ) were of the 2R configuration [as in erythratine (42)]. The alternative positional isomer [related to erysosalvinone (46)] was also identified in this study and named erysosalvine (45). Erysopitine (C,,H,,NO,) was isolated from E. uariegata L. and its structure (50) assigned from spectroscopic evidence (35).Conversion of 50 to erysotrine (1) (see Scheme 12) established the stereochemistry at C-3 and C-5, but the configuration at C-2 has not yet been defined. Of biogenetic interest (see Section V,A) was the isolation of erysodienone (58) along with N-norprotosinomenine (67) and protosinomenine (68) from E. lithosperma Blume (now E. variegata L.) (34,35).Erysodienone had been previously synthesised (54, 66, 6H), but this was the first report of its isolation

0 49 R’ 46 R’ 51 R’

= = =

H, RZ = CH, Erysotinone CH,, R Z = H Erysosalvinone R 2 = H Erysoflorinone

47 Dihydroerysodine

7 Erysodinc

SCHEME 10

49 Erysotinone

48 Erysotine

(

+ C-2 epimer) SCHEME 11

39 Erythratidine

1.


21

CH,O

HO

OH 50 Erysopitine

1 Erysottine

SCHEME 12 HO

0

CH30 cH30?R OH

58 Erysodienone

67 R = H 68 R = C H 3

from plant material. Identification of 58 was made by comparison of its melting point and spectroscopic properties with the reported data and by reduction to the known transformation product erysodienol(35).

5. Abnormal Alkaloids from Cocculus Species Only 3 of the 12 species of Cocculus (Menispermaceae) have been examined for alkaloids and most studies have concerned C. laurifolius, which has yielded the greatest number of alkaloids (see Table I) (51, 55-58,60, 69-76). The Erythrina-type alkaloids obtained from Cocculus are abnormal in the sense that they contain no oxygen function at C-16, the only exceptions being dihydroerysovine (44), dihydroerysodine (47), and erythroculine (53). Erythroculine is, however, unusual in that it has a methoxycarbonyl group at C-16. The two alkaloids isococculidine (36) and isococculine (37) are of the A2( 1)-alkene type rather than the A1 (6)-alkene type. The insecticidal alkaloid cocculolidine (61), a lower homolog of B-erythroidine (60) (see Fig. 4), was mentioned in the previous review ( 1 ) where its isolation from C. trilobus DC was reported. It has now been isolated from C. carolinus DC, a species native to the Southeastern United States (69).

22

S. F. DYKE A N D S. N. QUESSY

TABLE I ERYTHRIXA ALKALOIDS FROM mP( C )

Alkaloid Cocculine

Isococculine Cocculidine Isococculidine Coccutrine Coccoline Coccolinine Coccuvine Coccuvinine Erythroculine Cocculitine Dihydroerysovine Dihydroerysodine Cocculolidine

217-218

COCCLLUS SPECIES

[.ID

Plant source‘

+271

~

86-87 (93-95) 95-96 263 -265 245-246 174- 175 137-1 38 103- 104 193-196b.C 142-1 43 h

208-209 144- 146

+ 260 + 124 + 232 + 233 ~

+ 194 + 93 + 233 + 224 + 273

Ref.

A B C A A A B

51,55

A

55

A A A A A B A B C

71 72

60 h9

70 51, 55, 58

55 60

56

73 74 57 75 76 69

“A. C. luurfolius DC (leaves); B, C. trilobus DC (leaves); C, C. carolinus DC (fruits). Oil. Styphnate.

Cocculine (C, , H 2 , N 0 2 ) and cocculidine (Cl8H2,NO,) were isolated from C. laurijolius in 1950 (77) but escaped mention in previous reviews of this treatise because only a partial structure, unrelated to the Erythrina alkaloids, had been advanced (78). On the basis of the spectroscopic properties of the alkaloids and their Hofmann degradation products, structures 56 and 54 (without stereochemistry) were proposed for cocculine and cocculidine, respectively (79); however, a different group (80) proposed structures 69 and 70, respectively, on the basis of similar evidence. The

CH,O’ 56 R = H Cocculine 54 R = CH, Cocculidine

69 R = H 70 R = C H ,

1.

E R ) TliRI,\ A A N D RELATED ALKALOIDS

23

AcO

56 Cocculine

71

SCHEME13

former group established the spiro structure of 56 by conversion to the 0 , N diacetate 71 (51) (see Scheme 13), and X-ray analysis of the hydrobromide salts of 56 and 54 established the structures originally proposed (51, 52). Although the absolute stereochemistry was stated to be 3 R 3 the structures were ambiguously represented as the mirror image of this configuration. A rigorous definition of the absolute configuration of cocculine was reported by McPhail and Onan in 1977 (49) whereby stereostructure 56 (i,e., 3R,5S9 was established for cocculine. It follows that cocculidine has stereostructure 54 since it has been demonstrated that methylation of cocculine using diazomethane gives cocculidine (77). Cocculine has also been isolated from C. trilobus (60)and C. carolinus (69).

52 Coccutrine

53 Erythroculine

A related alkaloid coccutrine (CI8H,,NO,) was isolated from C. trilobus (60)and structure 52 established spectroscopically, with the positions of the aromatic hydroxyl and methoxyl groups being defined by X-ray analysis. Coccutrine is the only example of an Erythrinu alkaloid containing an oxygen function at C- 17. An unusual alkaloid, erythroculine (C,,H,, NO,) was obtained from the leaves of C. luurifolius (67)and its structure (53) deduced from spectroscopic and degradative evidence (73). The MS data were consistent with a Al(6)alkene structure and the IR spectrum exhibited an absorbance at 1710 cm-'. The N M R spectrum established the presence of three methoxyl groups and two para-oriented aromatic protons. Reduction of 53 gave erythroculinol

53 Erythroculine

I

BC'I, CH,CI,

74

72 Erythroculinol

!

(I) AC,O ( i t ) yon Braun (iii) L A H (iv) CH,O,'NaBH,

&

NCH3

73

SCHEME 14

75

1.

25

E R Y T H R l N A A N D RELATED ALKALOIDS

(72) (see Scheme 14) which contained an IR absorption attributable to a hydroxyl group, but no carbonyl band was observed. Since one of the methoxyl groups in the NMR spectrum had disappeared, a methoxycarbonyl group was established. Demethylation of 53 gave a phenolic base 73 (Scheme 14)which showed a large bathochromic shift in the UV spectrum. This led to the assignment of the methoxyl function in 53 ortho to the methoxycarbonyl group, and the position of these groups was made on the basis of detailed NMR studies, including the observation of deuterium exchange ortho to the methoxyl group in erythroculinol. The environment of the nitrogen atom was established by Hofmann degradation of 72 (Scheme 14) and spectroscopic analysis of the degradation product 74. Erythroculinol was degraded by a combination of von Braun and Hofmann methods (see Scheme 14) to the biphenyl 75, whose structure was proved by an unambiguous synthesis. Finally, the stereochemistry at C-3 and C-5 was established by transformation of erythroculine (53) to tetrahydroerysotrine (76) as shown in Scheme 15. The presence of the methoxycarbonyl group in 53 is interesting from a biogenetic point of view.

i

53

performic acid

76 Tetrahydroerysotrine SCHEME 15

Continued examination of the pharmacologically interesting species C. laurifolius, particularly by Singh et al. (55,56,70-72, 74) has led to the isolation of more Erythrina alkaloids that have structures related to cocculine (56) and cocculidine (54). Coccuvine (C, 7H19N02) and coccuvinine (C,,H,,NO,) were found to be of the 1,6-diene type (56, 72) and the structures 16 and 14, respectively, were established on the basis of spectroscopic evidence and chemical interconversions. Methylation of coccuvine (16) (see

26

S. F. D Y K E AND S. N. QUESSY

Scheme 16) gave coccuvinine (141, which was reduced catalytically to give cocculidine, the structure and absolute stereochemistry of which was already established. The 8-0x0 counterparts of both coccuvine and coccuvinine were also isolated and given the names coccoline and coccolinine. Structures 17 and 15 (see Fig. 2) were assigned on the basis of spectroscopic studies including detailed examination of NMR spectra (55, 71). In addition methylation of 17 gave 15. The stereochemistry at C-3 was determined from coupling-constant data (see Section II,C,2d)and the configuration at C-5 was assumed. It was suggested, however, that 17 and 15 were artifacts produced during the drying process.

HO

9% CH,O p

&izHH1,

-

CH,O~’

’

16 Coccuvine

CH,O

-;I

-

CH,O-’

’

CH,O,’

14 Coccuvinine

54 Cocculidine

SCHEME16

Two further alkaloids, isococculine (C, ,H2 NO2) and isococculidine (C, sH2,N02),were isolated and found to be isomeric with cocculine 56 and cocculidine (54), but were discovered to have novel structures with respect to the position of the double bond (55, 70). Structures 37 and 36 for iso-

37 R = H Isococculine 36 R = CH, Isococculidine

55 Cocculitine

cocculine and isococculidine, respectively. followed from the analysis of the physical data. For example, the UV spectrum of 36 showed an isolated double bond, but the MS fragmentation pattern was similar to that of the 1,6-diene Erythrina structure rather than the A1(6)-alkene type. The A2(1)alkene structure was supported by the NMR spectrum which exhibited two olefinic protons at 6 6.06 and 5.85 ppm ( J , , 2 = 10.5 Hz). The absolute stereochemistry was not determined since a correlation between 36 and cocculidine (54) through their dihydro derivatives was not possible because

1. t R > THRl.tA

A N D RELATED ALKALOIDS

27

of the resistance of 54 to hydrogenation (55).However, the configurations at C-3 and C-6 were supported by coupling-constant data obtained from the NMR spectrum. A new alkaloid cocculitine (C,,H,,NO,) was isolated recently from C. laurijolius (74). The IR spectrum indicated the presence of a hydroxyl group (3460 cm- ’) which was further established by the formation of a mono-O-acetate (1715 cm-I). The NMR spectrum of cocculitine was very similar to that of erythratine (42),except in the aromatic region. The aromatic methoxyl group was located at C-15 on the basis of detailed decoupling experiments, and the stereochemistry at C-3 was determined from the coupling data, which suggested that the proton at C-3 was axial. A value of 8.5 Hz for J,,, suggested that the proton at C-2 was also axial and hence structure 55 was proposed for cocculitine. Only two “normal” Erythrina alkaloids have been isolated from Cocculus species, dihydroerysodine (47) (75) and dihydroerysovine (44), the latter recently from C. trilobus (57).Neither alkaloid has been found in Erythrina species. The structure 44 for dihydroerysovine was deduced from the spectroscopic evidence and by methylation using diazomethane to give the known dihydroerysotrine (38). The positions of the aromatic substituents were determined by detailed N M R experiments using NOE and INDOR techniques (see Section II,C,2d).

47 Dihydroerysodine

44 Dihydroerysovine

111. Homoerythrina Alkaloids

A. OCCURRENCE AND ISOLATION The C-Homoerythrina alkaloids are a relatively recently identified group, the first examples being isolated and identified from Schelharnnzera ~ ~ ~ u F. ~MueI1. c uin /I968 ~ (81). ~ ~Homoerythrina alkaloids have been isolated from all three species of Schelhanziwera (Liliaceae), in which they constitute a further addition to the various biosynthetically related alkaloids within the family Liliacea (82-85); from the leaves of species of Phelline (Ilicacea), where their presence raises some doubts about the taxonomic classification of the genus (86-88); and from the roots and stems of species

28

S . F. DYKE AND S . N. QUESSY

of Cephalotaxus (Cephalotaxaceae), particularly C. wilsoniana Hayata in which they are the major alkaloids (89-91) (see Table 11). Many members of the Homoerythrina group occur with their C-3 epimers, in contrast to the Erythrina group, and despite the fact that they appear in relatively few plant species, over 20 individual Homoerythrina alkaloids have been isolated, although the structures of two of them remain incomplete because of insufficient amounts of samples. Those alkaloids of known strucTABLE I1 PHYSICAL PROPERTIES OF HOMOERYTHRINA ALKALOIDS

Alkaloid

Formula

m P ( C)

88 89 8-Oxoschelhammeridine 1 la-Oxoschelhammeridine Schelhammeridine 3-Epischelhammeridine 86 (Alkaloid 6) Schelhammericine 3-Epischelhammericine

186-1 88 133 170-171 151 -173 118 131-133 126 76-77 169-172' 170- 17I'

Ma (Alkaloid A)

188-1 89c 260d 173- 174 182-185 184-185 e 152-153 150-152 150-151 244 decd e e I43 -145' 100-1 01

~

84b (Alkaloid 1) Schelhammerine 3-Epischelhammerine 96 83 (Alkaloid B)

Wilsonine 3-Epiwilsonine 82a 82b 85 (Alkaloid 2) 97 (Alkaloid 5)

[.I; f 143

+ 140

+ 35

- 41

108 f24 f63 +I22 f 123 +98 I23 - 100 15 186 + I67 172 f76r +I11 +115 -51 58 +I18 + 122 72 +91

-

+ + + +

+ +

Plant sourceh (Ref.) E E A A A A D A A, B, C D F, G A D A A D F A, C F G D F F, G D D

Solvent: chloroform. A, S . peduncula/a F. Muell: B, S. niul/iflora R. Br.; C , S. Uiidulatu R. Br.. D. P. coniosa Labill: E. P. billardieri; F. C. harringroiria K. Koch var. hurr.iiiy/oiiiu: G, C. wilsoniuna Hay. Picrate. Hydrochloride. Noncrystalline. Doubtful value due to impure sample.

1.

29

ERYTHRINA AND RELATED ALKALOIDS

ture are shown in Figs. 6 and 7. Within the three genera, the alkaloid profile is fairly distinctive, with only 3-epischelhammericine (81b) occurring in all three. The alkaloids have been isolated either by alcohol extraction of the dried plant material (82,90) or by ether extraction of the basified plant material (87). The crude mixture is then fractionated by countercurrent distribution, followed by chromatographic purification and recrystallization. The Homoerythrina alkaloids have not been reviewed before, except briefly in conjunction with Cephalotaxus alkaloids, with which they occur in Cephalotaxus species (9). Y

R' 77a 77b 78 79

Schelhammeridine 3-Epischelhammeridine 8-Oxoschelhammeridine 1 la-Oxoschelhammeridine

R2

-CH2-CH2-CH2-CH2-

R3

R4

X

Y

CH,O H CH,O CH,O

H CH,O H H

H, H2 0 H2

H2 H, H2 0

PIG. 6a. Homoerythrina alkaloids: 1,6 diene series

R2

80a 80b 81a

81b 82a 82b 83

Schelhammerine 3-Epischelhammerine Schelhammericine 3-Epischelhammericine 3-Epi-2,7-dihydrohomoerysotrine 2,7-Dihydrohomoerysotrine 2.7-Dihydrohomoerysovine

R2

CH2 -CH,-CH2-CH,CH, CH, CH, CH, CH, H ~~

R3

R4

X

CH,O H CH,O H CH3O H H

H CH,O H CH,O H CH,O CH,O

OH OH H H H H H

FIG.6b. Homoerythrina alkaloids: Al(6) alkene series.

30

S. F. DYKE AND S.

N. QUESSY

RZO

k4 R1 84a 84b 85

R2

3-Epi-6~,7-dihydrohomoerythraline -CH,6~,7-Dihydrohomoerythraline -CH CH, CH, 6a,7-Dihydrohomoerysotrine

R3

R4

CH30 H H

H CH,O CH,O

FIG.7a. Homoerythrina alkaloids: A2(1) alkene series

R4 R' 86 87a 87b

R2

3~-Methoxy-l5,16-methylenedioxy-6,7-epoxy- -CH2C-homoerythrinan-2(1)-em CH, CH, Wilsonine CH, CH, 3-Epiwilsonine

R3

R4

H

CH,O

CH,O H

H CH,O

FIG.7b. Homoerythrina alkaloids: epoxy- A2( 1) series

88 R = H 89 R = CH,

90 Phellibiline'

FIG.7c. Homoerythrina alkaloids : the homoerythroidines.

B. NOMENCLATURE Nomenclature for the Homoerythrina group is a problem because only a few of the alkaloids have been given trivial names. Since the structures of the Homoerythrina group parallel those of the Erytlzrina group we have

1.

EK > 7 H R I . V A A N D RELATED ALKALOIDS

31

decided to refer to the unnamed members as homo analogs of the corresponding Erythrina alkaloid. This has the advantage of illustrating the structural relationship between the two groups (as they are biogenetically related) and keeps the names relatively simple. When this is not possible the Chemical Abstracts system, which is based on the C-homoerythrinan ring 91, is used. We have used the Chemical Abstracts numbering system for the sake of consistency, even though it differs from that used in the literature (cf. 92).

11 6 % :s

14

7

3 2

91

2

92

C. STRUCTURE DETERMINATION 1. Spectroscopic Characteristics

In many ways the spectroscopic properties of the Homoerythrina group parallel those of the Erythrina series (cf. Section II,C,2). The UV and NMR characteristics are similar, particularly in rings A and B. The mass spectra of the 1,6-diene series show a simple fragmentation pattern, similar to that in the Erythrina 1,6-diene series, with the major fragmentation pathway involving loss of the allylic substituent (see Scheme 17). The A1(6)-alkene series shows a more complex fragmentation pattern, as do their A1(6)-alkene Erythrina counterparts. The same retro-Diels-Alder fragmentation occurs, but other important modes of fragmentation are initiated in ring C (see Scheme 18). As in the Erythrina group, the stereochemistry at C-3 may be assigned from coupling constant data; however, chemical shift data can also be used as an indicator of stereochemistry. For example, in the schelhammericine (81a) series (3S-methoxyl), the methoxyl resonance occurs at 6 2.74 ppm

32

S. F. DYKE AND S . N. QUESSY

Ic SCHEME

I

-CH,OH

18. Major fiagmentation pathway f o r A I ( 6 ) d k e n e - t y p eHomoerythrina alkaloids

with a quartet for the axial C-4 proton near 6 1.78 ppm. In the 3-epischelhammeridine (81b) series (3R-methoxyl), the methoxyl resonance occurs at 6 3.17 ppm, with an apparent triplet for the axial C-4 proton around 6 1.52 ppm. 2. Schelhammerine, Schelhammeridine, and Their C-3 Epimers The structural determination of the first Homoerythrina alkaloids, obtained from Schelhammera, was the subject of an elegant series of papers by the CSIRO group in Australia (81-85). Two major alkaloids from S. peduncufata F. Muell. were named Schelhammerine (C, ,H,,NO,) and ~ c h e l ~ a ~ ~ (CI9H2,NO3) e ~ ~ ~ i n e(82). The alkaloids had similar NMR characteristics in that both exhibited resonances attributable to a methylenedioxy group, a nonaromatic methoxyl group, and two para-aromatic protons ; but schelhammeridine contained two olefinic protons in its N M R spectrum and exhibited an isolated alkene absorption in the UV spectrum, whereas schelhammerine showed absorption arising from only one olefinic proton in the NMR spectrum, and the extra oxygen atom was found to be in a hydroxyl group. Furthermore, treatment of schelhammerine in pyridine with methanesulfonyl chloride gave schelhammeridine in 20% yield (see Scheme 19), revealing that the two alkaloids were structurally related. Since the nitrogen atom was tertiary, and evidence for N-methyl was not observed, a tetracyclic system was considered. The possibility that the fused heterocyclic rings were both six-membered was excluded through analysis

1.

E R Y 7 H R / , C A A N D RELATED ALKALOIDS

80a Schelhammerine

33

77a Schelhammeridine (20"f; yield based on recovered 80a)

SCHEME 19

of the signals for the C-7 and C-8 protons in the NMR spectrum of schelhammeridine, which clearly indicated a five-membered ring. The complete structure of schelhammerine (except for stereochemistry at C-2 and C-5) was deduced as 80a from a careful analysis of its 100-MHz NMR spectrum, with the aid of decoupling experiments. Values of 5.0 Hz for J3,4eq and 3.2 Hz for J3,4ax suggested that the proton at C-3 was equatorial; but a value of 3.0 Hz for J 2 , 3did not allow definitive assignment of the stereochemistry at C-2, although it suggested that the proton at C-2, was also equatorial. The absolute stereochemistry (as shown in 80a) was established by X-ray analysis of schelhammerine hydrobromide (92). The stereochemical assignments made from the NM R spectrum were further supported by the isolation of an alkaloid (alkaloid H) isomeric with schelhammerine, with similar UV and identical MS spectra. A value of 12 Hz indicated that the proton at C-3 was axial, but lack of large transfor J3,4ah diaxial couplings for J 2 , 3 suggested that the hydroxyl group at C-2 was axial, as in 80a. The alkaloid therefore had the structure 80b and is 3-epischelhammerine. The assignment of structure 77a for schelhammeridine followed from the NMR analysis and from the interconversion reaction (Scheme 19), which also established the absolute configuration at C-3 and C-5. In addition, a minor constituent (alkaloid G) was isolated, isomeric with 77a, having idenThe alkaloid tical UV and MS spectra but with a value of 11 Hz for J3,4ax. therefore appeared to be 3-epischelhammeridine (77b), demonstrated by a series of interconversions summarized in Scheme 20. Vigorous hydrolysis of 77a in acid gave a complex mixture of products, the major one being the alcohol 93, That epimerization at C-3 had occurred was evident from the values of 3.5 and 12 Hz for J3,4in the N M R spectrum. A minor product with values of 2.0 and 4.8 Hz for J3,4was found to be the alcohol, with retention of configuration at C-3. Methylation of 93 gave 77b, and conversely acid hydrolysis of 77b gave 93 thus establishing the configurations at C-3 and C-5 in 77b (83).

34

S. F. D Y K E AND S.

77a

N. QUESSY

93 (70“,) ( + C-3 epirner lo“,)

77b

SCHEME 20

The two isomeric alcohols 94a and 94b were isolated and identified among the minor products of the hydrolysis reaction. This finding revealed that

94a R’ = OH, R 2 = R 3 = H 94b R’ = R’ = H, R 2 = OH 94c R’ = OAc, R 2 = H, R3 = AC

the “apo rearrangement,” which occurs on acid hydrolysis of the Erythrina alkaloids, does not occur with the Homoerythrina group, where a bridged biphenyl system is formed. The ease of cleavage of the N-C-5 bond in schelhammeridine is also unparalleled in the Erythrina series. When schelhammeridine was heated at reflux in acetic anhydride a single stereoisomer 94c was obtained. It was then shown that the stereochemical outcome of the acid-hydrolysis reaction was temperature-dependent, because of limited rotational freedom of the biphenyl system. Hydrogenation of schelhammeridine (77a) in acetic acid gave rise to five products, and the structures of four of them were determined spectroscopically (83). The two major products were the 2,7-dihydro- and the tetrahydro derivatives 81a and 95, respectively (see Scheme 21). Hydrogenolysis and N-C-5 bond cleavage products were also observed. It was found that the yield of the dihydro derivative 80a was increased when ethanol was used as the solvent for the hydrogenation. The 6a-configuration in 95 was assigned on the assumption that hydrogenation would occur from the less hindered a-side of the molecule. In the Erythrina group, this assumption proved to be incorrect ( I ) , so the configuration at C-6 in 95 and in the A2( 1)dihydro series (Section 111,C,5) remains to be proved.

1.

E R Y T H R I V A A N D RELATED ALKALOIDS

77a

35

81a (30',,) (Schelhammencine)

SCHEME21

3. Oxoschelhammeridines Two alkaloids (C,,H,,NO,) were isolated from S. pedunculata, of which one was a base and the other was nonbasic (84). The base (alkaloid J) exhibited an IR absorbance at 1665 c m p l and UV absorbances at 232 (3,100), 277 (4,600) and 313 nm (5,000), suggesting an aryl ketone. Comparison of its NMR spectrum with that of schelhammeridine revealed a lack of C-1 1 methylene protons and a downfield shift of the C-17 proton. The ketone function was therefore located at C-lla. The stereochemistry at C-3 was assigned from the value of 4.0 Hz for J3,4ax and the configuration at C-5 was assumed. Structure 79 was proposed for the basic alkaloid, which is therefore 1 1a-oxoschelhammeridine.

The NMR spectrum of the nonbasic alkaloid (alkaloid K) showed the C-7 olefinic signal as a singlet, in contrast to the usual multiplet, and there were no signals attributable to the protons at C-8. A downfield shift observed for the protons at C-10 was consistent with the expected deshielding effect of a carbonyl group at C-8, which also accounted for the nonbasic nature of the alkaloid. An intense IR band at 1685 c m p l also supported the lactam structure 78. The value of 5.0 Hz for J3,4ax supported the stereochemical assignment at C-3, but rigorous proof of the structure 78 was obtained by oxidation of schelhammeridine using mangenese dioxide to give 8-oxoschelhammeridine (78) (see Scheme 22). This established the configuration at C-5 and proved the stereochemistry at C-3.

36

S. F. D Y K E A N D S. N. QUESSY

CH,O

CH,O

78

77a Schelhammeridine

SCHEME 22

4. Schelhammericine and the A l(6)-Alkene Series Schelhammericine ( C ,,H,,NO,) was recognized as a A1(6)-alkene structure from its MS fragmentation pattern (see Section III,C,l) and structure 81a was determined through analysis of its NM R spectrum. Values of 3.5 and 5.0 Hz for J3,4 suggested that the proton at C-3 was equatorial. Schelhammericine was identified as the dihydro product 81a obtained on catalytic hydrogenation of schelhammeridine (refer to Scheme 2 1) (84). An isomeric alkaloid (alkaloid E) was isolated from S. pedunculata and found to be the major alkaloid in 5’. rnultzj2ora R.Br. (85). Values of 4.0 and 11 Hz for J3,4suggested that it was the C-3 epimer 81b of schelhammericine. Structure 81b was proved by identification of 3-epischelhammericine with 2,7-dihydro-3-epischelhammeridine(see Scheme 23) (84). Later on, another group reported the isolation of 81b from P.comosa, and was able to convert 3-epischelhammerine (80b) to 81b by chlorination and reduction, as shown in Scheme 23 (87). Cephalotaxus harringtonia var. harring ton ia has also yielded 3-epischelhammericine ( 9I ) .

(9 -.::-::Cy+ 0

-

CH,O,-

’

CH,O,’

CH,O,’

,

OH 77b 3-Epischelhammeridine

Slb 3-Epischelhammericine

80b 3-Epischelhammerine

SCHEME 23

Other alkaloids in the Al(6)-alkene series have been reported. Two isomeric alkaloids (C,,H,,NO,) were obtained from Cephalotaxus harringtonia K. Koch var. harringtonia. Their spectroscopic properties closely resembled those of schelhammericine except that their NMR spectra revealed the presence of two aromatic methoxyl groups in place of the methylenedioxy group of schelhammericine. The alkaloids were therefore 3-epihomo-2,7-

1.

E R YTHR/.\ 1 A N D RELATED ALKALOIDS

37

dihydroerysotrine and homo-2,7-dihydroerysotrine, with structures 82a and 82b, respectively. Distinction between the two epimers was made on the basis of the NMR data (see Section III,C,l). The configuration at C-5 was considered the same as that in schelhammericine, since their optical rotations were of the same sign and magnitude (89).

R4

82a R ' = R 2 = CH,, R3 = CH,O, R 4 = H 82b R' = R Z = CH,, R 3 = H, R4 = CH,O 83 R ' = CH,, R2 = R' = H, R4 = CH,O

An alkaloid (C,,H,,NO,, alkaloid B) isolated from S. pedunculutu exhibited UV characteristics similar to those of schelhammerine (80a) and an IR absorbance at 3600 cm-' suggested a phenolic hydroxyl group. The NMR spectrum was similar to that of 3-epischelhammericine and revealed the presence of one aromatic methoxyl group, a phenolic proton, and paraoriented aromatic protons. The position of the phenol group was located at C-15 by an NMR experiment that involved deuterium exchange of the aromatic proton ortho to the phenol group. The remaining aromatic proton was broadened because of benzylic coupling and was therefore at C-17. The stereochemistry at C-3 was deduced from the observation of a large value for J3,4ax, and the configuration at C-5 was assigned by the sign and magnitude of the optical rotation. The data were consistent with structure 83 for this alkaloid, which is therefore homo-2,7-dihydroerysovine (84). This same alkaloid was found in S. undulutu (85)and has also been isolated from C. harringtoniu var. hurringtoniu along with a similar base which, from its NMR spectrum was epimeric at C-3. However, the positions of the aromatic methoxyl and hydroxyl groups could not be defined because of a lack of pure sample, and partial structure 96 was proposed (89). H

CH,O' 96

97

38

S . F. D Y K E A N D S . N. QUESSY

An alkaloid (C2,H19N04, alkaloid 5 ) , isolated from Plicllinr c o m u a Labill., has a MS fragmentation of the A1(6)-alkene type. The N M R spectrum revealed the presence of three aromatic methoxyl groups, and the methoxyl group at C-3 was found to be equatorial from the large value of J3,4ax(1 1.5 Hz). The configuration at C-5 was assumed to be 5s on the basis of the sign and magnitude of the optical rotation. The partial structure 97 was proposed and it was suggested, on steric and biogenetic grounds, that the aromatic substitution pattern was 15,16,17-trimethoxy.

5. A2(1)-Alkene Series The first alkaloid of the A2(1)-alkenetype was obtained from S.peduncufata (84). An alkaloid (CI9H,,NO3, alkaloid A) was isolated that was isomeric

with both schelhammericine (81a) and 3-epischelhammericine (Sib), but which clearly contained an allylic methoxyl group, as indicated by the NMR spectrum and the ease of hydrolysis of the methoxyl group. Hydrolysis proceeded with inversion of configuration at C-3 to give alcohol 98 (see Scheme 24), the structure of which was supported by its NMR spectrum. Structure 84a was proposed for the alkaloid, and this was further supported by its reduction to a product identical with tetrahydroschelhammeridine 95 (see Scheme 25), which fixed the configurations a t C-3 and C-5, but the 6ci-configuration was assumed. The alkaloid 84a is therefore 3-epi-6~,7dihydrohomoerythraline. The C-3 epimer 84b ( 6 4 7-dihydrohomoerythraline) was not reported in S. pedunculata but was later isolated from P. C O ~ O S U(87). From its NMR 10"" HCI

10" HCI

A

(35"")

0

'H

'H

84a

98

84b

SCHEME 24. Relationship bertveen 84a and 84b.

84a

77a

95 SCHEME

25

1.

39

ER YTHRI.VA A N D RELATED ALKALOIDS

spectrum this alkaloid (alkaloid 1) was found to contain an allylic methoxyl group, and the coupling data suggested that the C-3 proton was axial. Hydrolysis of 84b gave the allylic alcohol 98 as the major product; this product had properties identical to those reported for the demethylation product of 84a (84)(see Scheme 24). The interconversion reactions outlined in Schemes 24 and 25 allowed the complete stereochemistry of 84b to be assigned. In addition, it was found that the von Braun degradation product of 84b was identical to that of 3-epischelhammeridine 81b (87),as shown in Scheme 26.

84b

81b

SCHEME 26

From the same plant a similar alkaloid (C,,H,,NO,, alkaloid 2) was isolated and found to differ from 84b in that it contained two aromatic methoxyl groups in place of the methylenedioxy group. The C-3 proton was, from the N M R coupling constants, found to be axial, and structure 85 was consistent with the data. The configuration at C-5 was assumed, although its CD curve was the inverse of that of 84b in the region 235 nm. Structure 85 corresponds to 6~~,7-dihydrohomoerysotrine. Two alkaloids, C,,H,,NO, and C,,H,,NO, (alkaloids 6 and 7), isolated from P.comosa exhibited similar NMR characteristics (87).Both contained an allylic methoxyl group, a disubstituted double bond, and para-oriented aromatic protons ; however, the former contained a methylenedioxy group and the latter two aromatic methoxyl groups. Their IR spectra showed the absence of hydroxyl or carbonyl functions, which suggested that the fourth oxygen atom was contained in a ring. The MS fragmentation patterns of the two alkaloids were almost identical, showing that they differed only in the aromatic substituents. Structures 86 and 87b, respectively, were assigned

CH,O. 85

R' 86

87a R' = CH,O. R Z = H 87b R' = H , R 2 = CH,O

40


to the two alkaloids from the spectroscopic evidence and on the basis of the transformations summarized in Schemes 27 and 28. Reduction of 87b using LAH gave the tertiary alcohol 99 with preservation of the double bond (Scheme 27). The position of both the double bond and the hydroxyl group was clear from the NMR and MS data of 99. The downfield shift experienced by the proton at C-14 (A6 1.36 ppm) could be accounted for if the hydroxyl group had the 68-configuration as this would place it spatially near the aromatic proton at C-14. Similar reduction of 86 gave the corresponding tertiary alcohol 100. Catalytic reduction of 87b gave rise to a secondary alcohol 101 as the major product. The MS and NMR data clearly revealed that isomerization of the double bond to the A1(6)-position had occurred. The signal for the methine to which the hydroxyl group was attached (i.e., C-7 proton) was located at 6 4.53 ppm by the use of N M R experiments involving deuterium exchange and acetylation. Irradiation of this signal produced a small (< 1 Hz) decoupling effect on the olefinic signal and a significant decoupling effect at the methylene protons attached to C-8. The data were consistent only with the hydroxyl group being attached at C-7, but the coupling values of 5.0 and 6.7 Hz for J7,* did not permit assignment of configuration. A similar reduction of 86 gave the secondary alcohol 102 which exhibited spectroscopic properties similar to those of 101. Further support for the structure of 102 was obtained from its

86 R + R = C H z 87b R = CH,

RO

OH CH,O”

OH

/

99 R = C H , 100 R + R = C H ,

101 R = CH,

102 R

+ R = CH2

1.

41

E R Y T H R l N A A N D RELATED ALKALOIDS I,) SOCI, 111)

LAH

A

(9 CH,O"

81b 3-Epischelhammericine

102 SCHEME 28

transformation to 3-epischelhammericine (Slb), as outlined in Scheme 28, which established the configurations at C-3 and C-5. That the original alkaloids 86 and 87b contained a 6,7-epoxy group was an inescapable conclusion of the reduction experiments; and the presence of such a group poses an interesting biogenetic problem. The stereochemistry of the epoxide remains uncertain. The alkaloid 87b was later isolated from C. wilsoniunu along with its C-3 epimer 87a (90). The name wilsonine has been given to 87a and 3-epiwilsonine to 87b. Since the alkaloid 86 has no trivial name and is not related to any members of the Erythrinu group, it is referred to here as 6,7-epoxy-3a-methoxy-15,16-methylenedioxy-C-homoerythrinan2(1)-ene.The structure of wilsonine was established in the way just described. 6. Homoerythroidines The two major alkaloids from P . billurdieri were found to have the chemical compositions C,,H2,N03 and C1,H2,N03. Their NMR spectra were similar, both contained a trisubstituted double bond but no aromatic protons. The former alkaloid exhibited one exchangeable hydroxyl proton, whereas the latter contained an aliphatic methoxyl group. The relationship between the two alkaloids was established when demethylation of the C,, alkaloid gave the C,, alkaloid. An absorbance at 1745 cm-' in the IR spectra suggested a 6- or elactone, an observation which was supported by LAH reduction to a diol (v,,,3450 cm-') in quantitative yield. The MS data suggested a A1(6)-alkene structure, and from the combined spectroscopic and degradative data the partial structures 103a and 103b were proposed

RO

-

103a R 103b R

=H = CH,

90

104

42

S. F. DYKE AND S. N . QUESSY

for the alkaloids. It was found that 103a isomerized on column chromatography to a product for which either the partial structure 90 (without the stereochemistry) or 104 was deduced. Structure 90 was favored on biogenetic grounds and on consideration of the N M R spectrum (88). The complete structure of this base, named phellibiline, was established by X-ray analysis, which revealed the absolute configurations at C-3, C-5, and C-12 as shown in stereostructure 90 (93).Since 90 was derived from the naturally occurring hydroxylic alkaloid and since this alkaloid has been related to its 0-methyl analog, structures 88 and 89 could be assigned to them. Aland the two major kaloid 89 is therefore 2,7-dihydrohomo-P-erythroidine,

88 R = H 89 R = CH,

alkaloids from P. billardieri are the only examples of the homoerythroidine series yet isolated.

IV. Cephalotaxus Alkaloids A. OCCURRENCE AND ISOLATION Cephalotaxus is a genus of plum yew natural to Eastern Asia, although it is now cultivated in many parts of the world (94). There are about seven species and most have been examined for alkaloids, which have been obtained from all parts of the plants. Since the alkaloidal extracts were reported in 1969 to exhibit antitumor activity (95), an intense investigation of the Cephalotaxus alkaloids has followed (8, 9). Most of the isolation work, structural elucidation, and pharmacological assay has come from the Northern Regional Research Laboratory in Illinois (8). The alkaloids were best isolated from the ethanol extract of the plant material, partially fractionated by counter-current distribution, and subsequently purified by preparative chromatography. Of the 11 known Cephalotasus alkaloids (105-115 in Figs. 8 and 9), cephalotaxine (105a)is ubiquitous and the most abundant (up to 64% of the total alkaloid extract) in all species examined. C. wilsoniana Hay., which yields only minor quantities of cephalotaxine, is the exception, however ; it is rich in Homoerythrina alkaloids,

1.

43

E R Y T H R I Y A AND RELATED ALKALOIDS

OR3

Cephalotaxine Epicephalotaxine Acetylcephalo taxine Harringtonine Homoharringtonine Isoharringtonine Deox yharringtonine Desme thylcephalotaxine Cephalotaxinone

105a 105b 106 107 108 109 110 111 112

R’

R2

R3

HO H CH,CO a b

H HO H H H H H H

CH, CH, CH, CH, CH3 CH, CH, H CH3

C

d HO

0

co-o-

“ t

a = CH,-C-(CH,),

OH

CH,

OH b

= CH,-C-(CH,),+OH

I

CH,CO,CH,

CH,COzCH,

CH, b

U

CO-O-

H

= CH,-~--(CH,),&OH

CH,

CO-O-

H

H d

9

CO-O-

= CH,-C-(CH,),-OH

OH

I

CH,

CH,COzCH3

CO,CH, d

1

F I ~8.. Ceptiaiofa.xus alkaloids.

OCH, 113 Desmethylcephalotaxinone

OCH, 114 1I-Hydroxycephalotaxine

FIG.9. Ceplialotauus alkaloids.

OCH, 115 Drupacine

44


companion alkaloids in Cephalotaxus species (90).Seven Homoerythrina alkaloids have been identified in Cephalotaxus, including 3-epischelhammericine (Sob), wilsonine (87a), 3-epiwilsonine (87b), and structures 82a, 82b, 83, and 96 (8). The other Cephalotaxus alkaloids are structurally related to cephalotaxine (105a)and the most important group are the harringtonines 107-1 10, which are C-3 esters of cephalotaxine, since they have antitumor activity (see Section VII). The harringtonines constitute less than 10% of the total alkaloid extract and are in greatest abundance in C. harringtonia K. Koch var. harringtonia (89). The demand for the harringtonines for use in clinical trials has exceeded their supply from natural sources, resulting in many attempts to synthesize them from the more abundant cephalotaxine (see Section V1,C). In a very recent examination of C. msnii Hook., a new antitumor alkaloid was isolated but found to be structurally unrelated to the usual Cephalotaxus alkaloids. In view of the chemical results the botanical classification of the plant is being reexamined (96). Recently, a GC-MS method for the separation and quantitative identification of extracts from Cephalotaxus species (97)has been described. Most of the alkaloids were resolved, particularly the biologically active esters. The seven Homoerythrina alkaloids were only resolved into two groups of five and two components, respectively, under the conditions described. Acetylcephalotaxine (106), 1 1-hydroxycephalotaxine (114), and desmethylcephalotaxinone (113) were not resolved by retention time, but could be identified within the mixture by their MS fragmentation patterns. Cephalotaxinone (112) gave two GC peaks after silylation, presumably due to a contribution from the enol component. The artifact peak overlaps partly with the peak for drupacine (115) and hence introduces a slight error for this component and makes it difficult to quantify cephalotaxinone. It has been observed that the melting points and optical rotations of several alkaloids differ by more than can be attributed to experimental variation and must thus depend on the plant source (9,89,98).The most striking example is cephalotaxinone which has [mID-57" (0.3 c/g cmP3, CHCI,), from C. harringtonia var. drupacea and [.ID - 125' (0.6 c/g cm-,, CHC1,) from C. harringronia var. harringtonia, but that obtained by oxidation of cephalotaxine has [.I, -155" (0.63 c/g ern-,, CHCI, (89, 98). It has been suggested that Cephalotaxus alkaloids may occur as partial racemates. Although cephalotaxine is optically active ([.], - 183"),its crystalline methiodide is racemic. The amorphous residue was found to be optically active ( [ a ] , 1127, and it was suggested that racemization occurred during recrystallization from hot methanol (99).It is not clear whether Cephalotaxus alkaloids do occur as partial racemates or whether some racemization occurs

+

1.

ER YTHRINA AND RELATED ALKALOIDS

45

during the isolation and purification procedures. It has been noted that cephalotaxine obtained by transesterification of deoxyharringtonine (110) has the same optical rotation as natural cephalotaxine, and yet the harringtonines do not occur as diastereomers. If cephalotaxine does occur as a partial racemate, then the acyl portion of the harringtonines should also be partly racemic, and this would have some significance in structure-activity studies (9, 100).

B. STRUCTURE DETERMINATION 1. Cephalotaxine and Epicephalotaxine Pure cephalotaxine was first isolated from C. fortunei Hook. and C. harringtoniu var. drupacea [formerly referred to as C. drupacea ( I O l ) ] (102). The pioneering work on the structure of cephalotaxine (C,,H,,NO,) was reported in 1963 by Paudler et ul. (102, 103), and on the basis of chemical and spectroscopic evidence structure 116 was tentatively proposed. The fact that the olefinic proton appeared as a singlet in the NMR spectrum was rationalized by proposing a dihedral angle with the adjacent proton of 90" and hence zero coupling. Powell et al. (104) reexamined the structure of cephalotaxine and suggested two structures, 105 and 117, which accommodated all the data, although the former structure was favored on biogenetic grounds.

116

OCH, 105

117

46


In an accompanying publication (105), the X-ray crysial structure of cephalotaxine methiodide, which proved structure 105 for cephalotaxine, was reported. Although the methiodide was prepared from optically active ([.ID - 183”) cephalotaxine, the crystalline product was racemic, so that only the relative stereochemistry was obtained. It appears that all four chiral sites in the methiodide undergo inversion, presumably by facile cleavage and re-formation of the N-C-5 bond. This could also explain the early difficulties in the structural elucidation by chemical transformation. Recently, the absolute configuration has been established by X-ray analysis of cephalotaxine p-bromobenzoate (99, 106) as 3S,4S,5R (as shown in 105a). The seven-membered heterocyclic ring exists in a boat conformation with the nitrogen atom at the prow. 17

11

OCH, 105a Cephalotaxine

A minor alkaloid from C. fortunei (98) showed an IR spectrum identical to that of cephalotaxine, but its melting point was depressed by it. The physical properties of this alkaloid were found to be identical to the minor product obtained by reduction of cephalotaxinone (112) using LAH (102). The alkaloid was therefore 3-epicephalotaxine (105b). Although a small amount of 105b was produced on reduction of cephalotaxinone with LAH, the use of borohydride or DIBAL-H gave only cephalotaxine (98). 2. Esters of Cephalotaxine During the structure elucidation work, cephalotaxine was shown to form a mono-0-acetate (106) (102), and this compound was later found as a minor alkaloid in C.fortunei (98).An impure sample of acetylcephalotaxine was also obtained from C. wilsoniana Hay. (90). When the alkaloidal extracts of C. harringtonia var. harringtonia were found to possess antileukemia properties, a search for the responsible alkaloids was initiated, since the major component, cephalotaxine, was inactive. Four alkaloids (the harringtonines) that exhibited anticancer properties were isolated. The structures of harringtonine, isoharringtonine, and homoharringtonine were reported in 1970 (107),and that of deoxyharringtonine was reported in 1972 (108).

1.

47


Examination of the NMR spectra of the harringtonines revealed a spectrum nearly identical to that of cephalotaxine as well as the presence of signals arising from a side chain. This observation led to the discovery that alkaline hydrolysis of the harringtonines gave cephalotaxine in each case, plus a complex dicarboxylic acid. This was further supported by the MS data, since each alkaloid exhibited a prominent fragmentation ion with nz/e 298, due to loss of the side chain (M' -OR). The same peak was observed in the MS of cephalotaxine (M' -OH). It was therefore established that the harringtonines were C-3 esters of cephalotaxine, differing only in the nature of the ester side chain. The structures of these side chains were deduced from a careful examination of the NMR spectra of their dimethyl esters, obtained from the natural alkaloids by transesterification using sodium methoxide in methanol (100, 107, 108). The number and nature of free hydroxyl groups was determined by examination of the NMR spectra in DMSO-d, before and after deuterium exchange. The N M R spectra of the esters obtained from harringtonine and homoharringtonine exhibited two equivalent methyl groups and two different carboxymethyl signals, two tertiary hydroxyl groups, and an isolated methylene group. The spectra were consistent with structures 118 and 119, respectively, for these diesters. The spectrum of the diester obtained from isoharringtonine differed in that it contained an isopropyl function, a singlet due to an isolated methine bearing a hydroxyl group, and only one tertiary hydroxyl group. Structure 120 was proposed for this diester. By a combination of IR and NMR evidence the diester obtained from deoxyharringtonine was found to contain only one hydroxyl group, which was tertiary, and structure 121 was consistent with the data. The structures of these diesters were confirmed by synthesis (see Section V1,C). C0,CH3

OH

CH,OZCpCH,-C~~(CH,),pCpCH,

OH

CH 3

118

H

C02CH3

CH,O,C-C-C-(CH,),

OH

OH 120

CO,CH, CHAOIC

CH,

7

OH

ICHZ),pCpCHA

OH

CHS

119

H -C-CH, CH,

C0,CH3

H

CH,O,C-CH,~C~(CH~),~~~CH; OH

CH,

121

The problem now remained as to which carboxyl group was attached to the cephalotaxine skeleton. The two possible half-esters, 122 and 123, were synthesized (see Section VI,C), and esterification of cephalotaxine with 122 gave rise to a mixture of diastereomers, neither of which was

48

S. F. DYKE AND S . N. QUESSY

CO,CH,

HO,C-CH,--C

(CH,), OH

H C - CH3

CH30,C-CHZ

CH3

122

CO,H

H

C-(CH2),

C -CH,

OH

CH,

123

CH,02C-CH,

H

CO

-

C

(CH,),-C-CH,

,

OH

CH3

124

identical to deoxyharringtonine (108). This result suggested that the tertiary carboxyl group was linked to cephalotaxine in deoxyharringtonine ; but all attempts to esterify cephalotaxine with the half-ester 123 failed, and it was concluded that both reactants were sterically hindered. It was found that in the MS fragmentation patterns of the half-esters, cleavage at the tertiary center was preferred. Thus, 122 and 123 exhibited M-CO,H (m/e 173) and M-CO,CH, (m/e 159) fragmentation ions in the ratios 1 :8 and 3: 1, respectively. Deoxyharringtonine showed a ratio ofmle 1731159 of 3:1, suggesting linkage through the tertiary carboxyl group (108). The structures of deoxyharringtonine and the other harringtonines have been proved by partial syntheses from cephalotaxine and are discussed in Section V1,C. The absolute configurations of the acyl side chains are also discussed in that section as they depend, in part, on stereospecific synthesis. Recently, tissue cultures of C. harringtonia var. harringtonia were found to yield Cephalotaxus alkaloids in the same ratio as the parent plant, although in lower total yield. It was hoped that this method would help to offset the shortage of harringtonines, since the alkaloids could be obtained after six months, whereas the Cephalotaxus tree was slow to mature. A new harringtonine was discovered in the culture. The GC-MS evidence suggested that it was a homolog of deoxyharringtonine, and structure 124 was proposed for the side chain from the MS data. The name homodeoxyharringtonine was suggested for the alkaloid (109). 3. 11-Hydroxycephalotaxine and Drupacine Two minor alkaloids (C1,H,,NO,), obtained from C. harringtonia var. drupacea (Sieb and Zucc) Koidz., were deduced to be 1 l-hydroxycephalotaxine (114) and its related ketal drupacine (115) (101, 104). The NMR spectrum of the former exhibited features similar to that of cephalotaxine, with the addition of a triplet at 6 4.78 ppm, which was part of an ABX system. The alkaloid formed a diacetate wherein the position of the methine

1.

49

ER YTHR1,VA A N D RELATED ALKALOIDS

triplet in the NMR spectrum shifted to 6 6.09 ppm. The AB part at b 3.26 ppm was assigned to the protons at C-10, hence the hydroxyl group was located at C-1 1. It did not prove possible to prepare 1 l-hydroxycephalotaxine from cephalotaxine because of the sensitivity of the C-3 hydroxyl group to oxidation, and therefore the configurations at C-4 and C-5 were assumed. Drupacine also exhibited an ABX pattern in its NMR spectrum, with a triplet centered at 6 4.87ppm. The position of this signal remained unchanged upon acetylation, which gave a mono-0-acetate. There was no olefinic signal in the NMR spectrum but geminal coupling in the methylene signals attributable to C-1 was observed. That drupacine is the 2,ll-bridged structure 115 was demonstrated by its preparation under mild acid conditions from 1 1-hydroxycephalotaxine (see Scheme 29). Furthermore, treatment of 114 with tosyl chloride in pyridine gave the 3,ll-bridged ether 125. These reactions require a cis relationship between the 1 1-hydroxyl group and the cyclopentene ring, so that the stereochemistry of the hydroxyl group in 11-hydroxycephalotaxine must be as shown in 114, where the hydroxyl groups are in close proximity. Further support for this assignment came from the finding that the diacetate of 114 could be readily epimerized at C-1 1, a reaction which obviously relieves the steric congestion.

OCH,

OCH,

114

11s

I OCH, 12s

SCHEME 29

50


The ready conversion of 114 to 115 suggested that drupacine might be an artifact produced during the isolation procedure. However, it was demonstrated that the isolation conditions could not account for all the material, so that some drupacine must be present in the plant (101). Both alkaloids are unique to C. harringtonia var. drupacea, and an alkaloid with properties similar to those of drupacine was also reported by Asada in the same species, although no structure was given (110). 4. Cephalotaxinone, Desmethylcephalotaxine, and Desmeth ylcephalo taxinone Cephalotaxinone (C, ,H ,NO,) was first isolated and characterized from C. harringtonia var. harringtonia (89) and later from C. fortunei (98). In the IR spectrum of this material, the hydroxyl group of cephalotaxine was absent but a carbonyl absorbance at 1720 cm-' was present. A shift in the olefinic absorbance from 1665 to 1625 cm-' suggested an enone structure. Cephalotaxinone was found to be identical to the product 112 formed by Oppenauer oxidation of cephalotaxine (105a) (see Scheme 30). This also established the stereochemistry of 112 at C-4 and C-5.

OCH,

OCH,

105a Cephalotaxine

112 Cephalotaxinone

SCHEME 30

Desmethylcephalotaxine (111) was first prepared by mild acid hydrolysis of cephalotaxine, during the early structure elucidation work (102). The same workers later identified this material as a minor constituent of C. fortunei (98). Desmethylcephalotaxine is not an artifact, since pure cephalotaxine can be subjected to the isolation procedure without loss. It was noted that chromatography of Ceplra~otasus alkaloid fractions over neutral alumina resulted in considerable losses (111). Further elution with dilute aqueous acetic acid resulted in the isolation of a new alkaloid, desmethylcephalotaxinone ([.ID + 2.3"). The IR spectrum of this alkaloid was consistent with the presence of a vinylic hydroxyl group (3520 cm-l) and a conjugated carbonyl group (1690 cm-I). The NMR spectrum obtained in deuterochloroform contained features of the cephalotaxine structure, but included a singlet attributable to an isolated methylene (6 2.54 ppm). In DMSO-d, this resonance appeared as an AB quartet. Acetylation

1.

51

ER Y 7 H R I N A A N D RELATED ALKALOIDS

produced an enol acetate, which exhibited a signal due to an isolated methylene at 6 2.59 ppm in the NMR spectrum. Structure 113 was established by interconversion reactions. Cephalotaxine was oxidized to cephalotaxinone (112) (as in Scheme 30) which, on vigorous hydrolysis in acid, gave desmethylcephalotaxinone ([.ID 40") in less than 30% yield after 3 hr at 80' (see Scheme 31). This material was identical to the natural product except for its optical rotation. It appeared that the natural product was nearly racemic since methylation gave optically inactive cephalotaxinone (see Scheme 31) plus a small quantity of the isomeric ether 126. The spectroscopic evidence suggested that desmethylcephalotaxinone exists in the tautomeric structure 113. The possibility that 113 was an artifact was considered unlikely under the conditions of isolation. The alkaloid has been found as a minor component in C. harringtonia var. harringtonia and in C. harringtonia var. drupacea ( I l l ) .

+

vigorous H *

'CH ,CH,CHIOCH,), , H

> +

0

OCH,

113 R = H Desmethoxycephalotaxinone 126 R = CH,

112 Cephalotaxinone

SCHEME 31

V. Biosynthesis A.

E R Y T H R ~ N AALKALOIDS

At the time of the last review in this treatise ( I ) very little was known about the biosynthesis of the Erythrina alkaloids. The essential postulate was that the aromatic bases are derived from tyrosine, with a phenolic coupling as a key step (Scheme 32) involving the symmetrical intermediate (127a) derived from 3,4-dihydroxyphenylalanine (DOPA). In one suggestion. oxidation of 127a to 128 (route 1, Scheme 32) and ring closure to 129, followed by cyclization to 132a was envisaged, whereas in the alternative proposal (route 2, Scheme 32) 127a undergoes phenolic coupling to 130a, followed by oxidation to the diphenoquinone (131a) and cyclization to 132a. The overall scheme was supported by the observation (66,112) that when 127a was oxidized with alkaline potassium ferricyanide ( )-erysodienone (58) was isolated in 35% yield. Mondon and Ehrhardt (66) also described the further in aitro conversion of (58)to ( f)-erysodine (7) via 133.

+

Tyrosine

L

DOPA

I

OH

R20

OH

OH

130

128

RZO

I

0

steps

131

HO 0

129 0

132

a : R, = R, = H b : R, = R, = Me

H

Me0 R'O 7

OH 133

SCHEME 32. A postulated biosynrhetic whet?ir.forErythrinu alkaloids

Hoq-$H 1.

58

-

53

E R YTHRf.VA A N D RELATED ALKALOIDS

%: :M

Me0

< H

Me0

/

Me0

QH 133

7

Since that time dramatic advances have been made in our understanding of the biosynthetic pathways to these alkaloids, almost entirely as a result of I4C-labeled feeding experiments. In an early study (113) [2-14C]tyrosine (34)was found to be incorporated equally at C-8 and C-10 of /l-erythroidine (60),a type of Erythrina alkaloid always believed (114)to arise from aromatictype compounds. This observation was regarded as a strong piece of evidence in favor of Scheme 32. Barton et al. (115) found acceptable levels of incorporation of 134 into erythraline (4), but when 127b, tritiated in the otherwise unsubstituted

mH;zH

HO

---+

o%*

-

MeO,'

134

60

4

positions ortho and para to the phenolic hydroxyl groups, was fed to E. crista galli very low levels of incorporation were found. It was concluded that a secondary amine such as 127 is not a precursor of the aromatic Erythrina alkaloids and an alternative biosynthetic route (Scheme 33) was proposed (115). In a key experiment (115) it was shown that (+)-(S)-norprotosinomenine (135) was incorporated into 4 100 times more efficiently than its enantiomer, strong evidence that 135 is a specific precursor of 4 (19,61,116).The intermediacy of 130b was also established (68).Interestingly, dibenzazonine alkaloids have been isolated from various erythrina species (21, 23). Furthermore, erysodienone (58) has been isolated (22, 23,34),

DOPA

Tyrosine

OMe

OH 136

135

I OH

OH

M

Me0

e/

o

g

\

H

Meox& /

Me0

OH

\

OH

130b

137

Me0 Me0 58 Erysodienone

138

Me0 OH SCHEME 3 3 . The biosynthetic route to the Erythrina alkaloids

1.

55

E R YTHRlh'A A N D RELATED ALKALOIDS

Me0

Me0

MeO"

0

Me0

0 48 Erysotrine

Me0

MeO'

MeO'

OH 42 Erythratine

140

I

I

i

J

Erysovine (5)

Erythraline (4)

+ Erysopine (9) + etc. SCHEME 33 (continued)

together with (S)-norprotosinomenine, from E. lithosperma (but see Section II,A about this species). When ['4C]4-methoxynorprotosinomenine was fed to E. crista galli, the erythraline (4) that was isolated was found to be equally labeled at the methoxyl and methylenedioxy group carbon atoms, thus confirming the involvement of a symmetrical intermediate such as 130b.

56


The important point concerning stereochemistry was also considered by Barton et al. (117, 118), who pointed out that the conversion of chiral 136 to 130b, thence into chiral erysodienone (as 139), must either involve an

139

inversion of configuration or a symmetrical intermediate. They showed (118) that chiral 130b is very rapidly racemized at room temperature and that only (-)-(55’)-erysodienone is the precursor of erythraline and of both a- and P-erythroidine. The biosynthesis of the “unusual” Erythrina alkaloids such as isococculidine (36), cocculidine (54),and cocculine (56) proceeds (119, 120) from (+)-

54 R = M e 56 R = H

(S)-norprotosinomenine (135).This was established (120) in feeding experiments with C. laurifolius DC. The proposed route is summarized in Scheme 34, where reduction of 136 to 141 was originally thought to occur, followed by a dienol-benzene rearrangement to 142. However, cyclization of 142 to isococculidine (36) is hard to visualize, although intermediate 143 was postulated. An alternative route (11a) involves reduction of the diphenoquinone 144 to 145, followed by cyclization to 146 and further elaboration to 36. The biosynthesis of z-and p-erythroidines has been investigated (118)by feeding 17-rnonotritioerysodine, 14,17-ditritioerysopine, and 1,17-ditritioerysodienone, when high levels of incorporation were observed, thus confirming that these lactonic alkaloids are derived in vivo from the aromatic compounds. The remaining point of ambiguity concerns the position of cleavage of ring D; the feeding experiments are compatible with either C-15-C-16 or C-16-C-17 cleavage, with the loss of C-16 and retention of tritium at C-17.

135

I 4

Me0 Me0

0 144

OH 141

I /

M Meo%H e0

\ OH 142

J.

/

M eO

MeO,'

0 143

36

58

S . F. DYKE AND S.

N. QUESSY

B. HOMOERYTHRINA ALKALOIDS The first two homoerythrina alkaloids to be isolated (82)were schelhammerine (80a) and schelhammeridine (77a), and since various species of

OH

80a

17a

Lilaceae also contain 1-phenethylisoquinoline alkaloids, it was suggested (82) that the homoerythrina derivatives are biosynthesized along a pathway analogous to that followed by the Erythrina alkaloids themselves (Scheme 35). Some preliminary results from feeding experiments (121) support this view; ( +)-[2-14C]tyrosine causes specific labeling of C-8 in 77a. ?H Me0

OH

I

OH

1.

59


C. C E P H A L O T AALKALOIDS XCS Arguing from structural similarities, it was originally suggested (10)that the Cephalotaxus alkaloids could be derived in viuo from the same precursor as the aromatic erythrina bases, but since Cephalotaxus and homoerythrina alkaloids have been isolated (90)from E. wilsoniana, it has been postulated (lob, 89) that both groups have a 1-phenethyltetrahydroisoquinoline as a common precursor (Scheme 36). Tyrosine is incorporated (122)into cephalotaxine, but the labeling pattern did not seem to be consistent with a

benzilic

rearrangement

RO

HO CO,H

0

.L

etc

SCHEME 36. Possible biosynrhetic route to the Ci~phulotaxusalkaloids.

60


OMe 105a

CO,H OH

0

acetyl-Co A

*C02H

&COZH

CO,H cephalotaxine

1

\COZH 110

S C H ~37. M ~Bios.vnthrsi3 uf dro.iy/turrittylottirtr

0

1.

E R YTHRl’VA AND RELATED ALKALOIDS

61

l-phenethylisoquinoline intermediate. Thus, [3-14C]tyrosine gave cephalotaxine (105a) with 68% of the activity at C-11 and 32% at C-4, but [2-14C]tyrosine labeled C-10 (37% of the activity); no label was found at C-7 or C-8. However, it was realized subsequently (123) that tyrosine was being catabolized, and the aromatic ring was not being incorporated into cephalotaxine. It was found (123)that phenylalanine is the precursor, in line with the derivation of other l-phenethylisoquinolines,and that ring D is derived from the aromatic ring of phenylalanine with the loss of one carbon atom. The biosynthesis of the acyl side chain of deoxyharringtonine (110) has been found (124) to involve L-leucine (Scheme 37).

VI. Synthesis A. ERYTHRINA ALKALOIDS A synthesis of erysotrine (1) was achieved by Mondon and his associates and reported in preliminary form in the previous review in this treatise (1). This work, which has now been published in full (125-129), is summarized in Scheme 38. Condensation of homoveratrylamine with the glyoxalate derivative of 4-methoxycyclohexanone gave the enamide (147) which, with phosphoric acid, was cyclized to the tetracyclic material (148). Reduction with Raney nickel followed by treatment with sulfuric acid gave the oxide (149) in which the rings A/B must be cis-fused. When 149 was subjected, after O-acetylation, to acid treatment, a mixture of two alkenes (150) was formed. These were separated and the correct one epoxidized to 151. Ring opening of 151 with dimethylamine yielded 152 which, on Cope elimination from the derived N-oxide, gave the alkene (153). Allylic rearrangement occurred when 153 was treated with acidified methanol to yield 154 as a mixture of epimers. These were separated by chromatography and each was carried through the remainder of the synthesis. Reduction of the amide carbonyl group of 154 gave 155, and this was followed by dehydration to 1. Finally, resolution of 1 was effected with dibenzoyltartaric acid to provide the (+)-isomer, identical with erysotrine obtained from natural sources. Mondon (125) was also able to convert the isomers (150), where the cis-A/B ring junction is established, to the dihydro derivative (156). This was then reduced to 157, where the A/B ring junction must be cis. Later, Kametani et al. (130, 131) reported that the tetracyclic compound (160) could be obtained as a mixture of cis-trans isomers merely by heating together the amine (158) and the ketoester (159). However, Mondon (132, 133) has cast doubt on this work and concludes that Karnetani’s product is

62


147 \

149

150

148

151

Me0

,

'OH

NMe,

153

152 SCHEME38. The ,first sythesis of erysotrine

1.

63

ER Y T H R I X A A N D RELATED ALKALOIDS

1.53

HC I !&OH

A

Me0

M e O ‘ U

154

I

( 1 1 separation 01 cpimeis

(111

LAH

Me0

“OH

155

1

SCHEME 38 (continued)

150

% Meo% Me0 ‘OH

Me0 Meo%

156

157

a mixture of the cis isomer (157) and the uncyclized material (161). Kametani et al. (131) also described the condensation of 158 with 162 and with 163 to form 164 and 165, respectively, but Mondon (132) concludes that these structures too are incorrectly assigned. HO Me0

159

160

64


Me0

U 161 158

164

165

A new approach to the synthesis of the Erythrina alkaloids involves (134) a Birch reduction of the amide (166) to 167, followed by cyclization, first to 168 with sulfuric acid in DMF, then to the ketolactam (169) with formic BzO

HO

Me0

Me0

T

N

M eO d

Me0 166

H

M

167

I

H,SO, DMF

98" HCO H

&

Me0

169

168

0

Y

e

1.

65

ER Y T H R I X A A N D RELATED ALKALOIDS

acid. When the isomeric amide (170)was subjected (135)to a similar sequence, the overall yield of 172 reached 90%. Ketalization of 172 with ethylene

Me0

170

171

I Me0e

O

y

$

+K;z:xFJ

MHe 0

(

H,SO,. DM F

O

0

0

L/ 172

173

/

(il Li+NR, lii) 0,

3'"' '

THF

(I)

M e0

e

0

Oxidation

f;":',

9 H

Me0

Me0

OH

H "OAc 0

LJ

175

174

i Me0

V

e

0

-9

+---

35""

MeO% Me0 'OAc

MeO"

/

1 Erysotrine

/

176

(I,) ill

m+ Meo%

HC'I MeSO,CI dcelone

Me0

Me0 OS0,Me

OH

O w 0

O w 0

177

174

85",,

!

NdOH MeOH

178

180

\

Zn HOAc

PhSeCl

";"-::6,. Me0

Y

Me0 CI

w

0

SePh C

I SCH,Ph

I

I

W

182

181

*

15"" H,Oi ps

loo",

i

Me0 182

179

SCH,Ph

Me0

4gYO. MrOH

RdNl

MeO"

MeO"

1.

67

ER YTHRINA A N D RELATED ALKALOIDS

glycol followed by 0-methylation gave 173, the lithium enolate of which was hydroxylated with oxygen to yield 174, which has the wrong stereochemistry at C-7. Epimerization was achieved by oxidation followed by reduction. Acetylation of the hydroxyl group and deketalization then yielded the ketoamide (175), which was reduced and dehydrated to 176. The conversion of 176 to erysotrine had been reported previously by Mondon and Nestler (136). The total synthesis of (+)-Erysotramidine (2) has been described by Ito et al. (137) starting from the amide (174) (Scheme 39). After 0-mesylation to 177, base-catalyzed reaction gave the cyclopropane derivative (178) which with zinc in acetic acid was reduced to 179, which was identical to the product (135) of 0-methylation of 172. Conversion of 178 to the thioketal(l80) was followed by reaction with phenylselenyl chloride. A mixture of two compounds, 181 and 182, was produced; the former could be transformed quantitatively to the latter. Finally, treatment of 182 with silver nitrate in methanol gave 183, which was then desulfurized to yield erysotramidine (2). An interesting short synthesis of the erythrane skeleton has been achieved by Wilkens and Troxler (138). Ethyl cyclohexanone-2-carboxylate was MeO.

L

M

o

e

w

,

Et 184

185

alkylated with ethyl bromoacetate, followed by condensation with homoveratrylamine to yield 184. Cyclization of 184 with phosphoric acid yielded 185. Stevens and Wentland (139) have prepared the erythrane derivative (187) by reacting the endocyclic enamine (186) with methyl vinyl ketone.

Me Meor rn i Meo”i-. -Meo +M e 0

Me0

O

POCI,

Me0

Me0

H

0 187

186

f

l

68

S. F. D Y K E AND S. N. QUESSY

The enamine (186) was itself prepared from homoveratrylamine and y butyrolactone. Yet another approach to the erythrane skeleton (140)involved Birch reduction of 6-methoxyindoline to 188, followed by N-acylation with 3,4-dimethoxyphenylacetyl chloride to yield 189. When this product was reacted with POCl, the ketoamide (190) was obtained in poor yield; the major product was 191.

Me0

rn 188

I 189

191

Synthetic studies along the biosynthetic route have attracted considerable attention. A very early success mentioned in the previous review ( I ) and in the biosynthesis section of this chapter (Section V,A) involved the oxidation of the diphenol(127a) with alkaline potassium ferricyanide to erysodienone (132a) via the benzocene (13Oa) and the diphenoquinone (131a) (Scheme 32). The mechanism of this reaction has been discussed by Barton et al. (68).The

1.

69


dienone (132a) has been converted to erythratine and dihydroerysodine (see Section V,A). A particularly interesting and useful synthesis of 130b has been described by Kupchan et al. (141-143), who oxidized the l-bemyltetrahydroisoquinoline (192, R = COCF,) with vanadium oxyfluoride (Scheme 40). Earlier Kametani et al. (144) had oxidized 192 (R = C0,Et) with potassium ferricyanide and had obtained 193 (R = C0,Et) in 2% yield. HO Me0

R

OH

OH

192

193

I

NaOH

130b

NaBH,

194

SCHEME 40. Kupchan's sjnthesis of bcvrxcenes

Oxidation of the 1-benzyltetrahydroisoquinoline(195) with VOCl, (145) yielded the dienone (196) in 34% yield; reaction of this with boron trifluoride etherate provided 197, and this was converted, as shown in Scheme 41, to 14-methoxyerysodienone (199). Oxidation of the secondary amine (200) gave (146)the methoxyerysodienone (201) in only 6% yield. The alternative mode of oxidation, leading to 202, was not observed.

70

S. F. DYKE AND S.

N. QUESSY

HO

Ms

Me0

Me0

OH

OH

195

196

I

63",, BF,IEt,O

OH

Meek ?H

Me0

M

e

o

w

\ Ms

w OH

OH 198

197

J

I99 SCHEME 41. Preparation of 14-metho~q.erq.sodienone.

A photochemical method has been employed by Ito and Tanaka (147) to synthesize erybidine (62) (Scheme 42). Irradiation of the bromoamide (203) gave a mixture of lactams 204 and 205. After chromatographic separation, the former was reduced and N-methylated to erybidine. Alkaloids of the erythroidine type have not yet been synthesized, but the parent ring system has been obtained (148) by the method summarized in Scheme 43.

1.

71

E R YTHRI.CA A N D RELATED ALKALOIDS

K,FelCNI,

Me0

Me0 OH 200

OMe

Hoq 201

Me0 \

0 202

OH I

Me0

Me0

\

Me0

SCHEME 42. S~ttrltesisof Er.rhidiltc. by pliorolFsis.

72


C:r

C0,Et

I

PhCHO

(iiJ HCILMeOH

v SCHEME 43. Preparation oj rlir e r j tliroidiiie skelerori.

B. HOMOERYTHRINA ALKALOIDS The ring system of the homoerythrina alkaloids has been prepared (149)by oxidative coupling of the 1-phenethyltetrahydroisoquinoline (206, R = COCF,) (Scheme 44). The diphenol (208) was obtained in 76% yield from 207, but all attempts to oxidize the N-trifluoroacetate of 208 to a diphenoquinone failed-probably because the two aromatic rings are orthogonal to each other. However, oxidation of the secondary arnine (208) itself with potassium ferricyanide gave a mixture of 209 (45”/d yield) and 210 (15%);

1.

73


5?M:e

‘OCF3

Me0 Me0

\

‘ OH

OH 201

206

I

(I) NaOH (11)

(111)

HCI NdBH,

OH

208

0 209

HO

M

e

00

9

210

SCHEME 44. Preparatiori of’ a honioer~.rl~ritia bF ozridarice coupling

these were separated by preparative thin layer chromatography. Sometime previously, Kametani and Fukumoto (150) described the oxidation of 206 (R = H) with potassium ferricyanide and assigned structure 210 to the product, but later they (151)altered this to 209.

74


The dienone (210) has also been prepared (152, 153) by oxidation of the amide (211) with potassium ferricyanide, when 212 was obtained in 67% yield. After protection of the phenolic hydroxyl group, reduction with LAH

211

212

removed the amide carbonyl and reduced the dienone to the dienol. Reoxidation and removal of the 0-benzyl group then yielded 210. An alternative preparation of 209 was described (152) in which 210 was converted (I) (11) (111)

BrCl LAH CrO,

Me0

210

89"o

eH

?H

I

chromous chloride

\

209 SCHEME 45. A n alternative preparation of 209

1.

75


to the amide (213)in 89% yield by reaction with chromous chloride; the amide (213), after 0-benzylation, reduction with LAH, and de-0-benzylation, gave the amine (208) in 53% yield. Finally, a 60% yield of 209 was realized when the diphenol 208 was oxidized with alkaline potassium ferricyanide (Scheme 45). Interestingly, when the dienone (207) is treated with BF,/etherate (154), rearrangement occurs to give the homoaporphine (214). Oxidation of the tetramethoxy-1-phenethyl-1,2,3,4-tetrahydroisoquinoline (215) with VOF, gave (142) a little of the dienone (210, together with a 64% yield of 217. However, when each was treated with acid, rearrangement occurred to give 218 and 219, respectively.

M::ycoc Me0Y Me0

Me0

\

OH

Me0

.6' OMe 215

214

OMe 0

M e 0P \ C

O

C

OMe

OMe

M:Ip 217

216

M

e

o

COCF,

Me0 OMr 218

OMe 219

w

F

3

76


c. CEPH.4LOTAXL.S

ALKALOIDS

1. Cephalotaxine The total synthesis of alkaloids of the cephalotaxine type has attracted considerable attention (75) because of the anticancer activity reported for certain derivatives (100) (see Section IV,A). The first synthesis of cephalotaxine (105a) was reported by Auerbach and Weinreb (155,156),closely

OMe 105a

followed by that of Semmelhack et al. (157-159) by a very different route. The former method can be conveniently divided into two stages, with the tricyclic enamine (225) as the first target; the route adopted is summarized

220

224

\

225 SCHEME 46. The prc'paration of the tricyclic enamine (225).

1.

77

ER Y T H R I N A A N D RELATED ALKALOIDS

in Scheme 46. Acylation of 1-prolinol (221) with 3,4-methylenedioxyphenacetyl chloride (220) at - 20" in acetonitrile solution gave the N-acylated compound (222), with only minor amounts of the 0-N-diacyl derivative. Oxidation of 222 to 223 was effected with dimethyl sulfoxide, dicyclohexylcarbodiimide, and dichloracetic acid. Cyclization of 223 to the tricyclic amide (224) was achieved using boron trifluoride etherate. The required enamine (225) was obtained in quantitative yield by reducing 224 with lithium aluminium hydride. The second phaseof the synthesis by Auerbach and Weinreb wasconcerned with the construction of ring D. This proved to be rather difficult and initial attempts failed. Thus, alkylation of 225 with propargyl bromide gave 226, which upon hydration with aqueous mercuric sulfate yielded the expected ketone 227. However, all attempts to cyclize 227 failed. In a modified 225

(9 (9 0

226

I

Me0

C0,Et

228

0A C H ,

227

approach, 225 was alkylated with 4-bromo-3-methoxycrotonate, but again the alkylated material (228) could not be cyclized. The a-dicarbonyl compound (230)was prepared (Scheme 47) by acylating 225 with a 2-acetoxypropionyl chloride in acetonitrile to give 229, which, after hydrolysis with potassium carbonate, was oxidized to 230 with lead dioxide. In a better procedure, wherein 230 was obtained directly in 73% yield, the tricyclic enamine (225) was treated with the mixed anhydride obtained from the interaction of pyruvic acid with ethyl chloroformate. An intramolecular Michael addition was achieved by treating 230 with magnesium methoxide,

78


(yq-&-<W 0

0

AcO

P-

229

&Me 0 230 52“,

I

Mg(OMe),

0

231

112 Cephalotaxinone

SCHEME 47. Auerharh and Weinreb‘s synthesis of rrp/ialora\-ine.

leading to demethylcephalotaxinone (113). A study of the N MR spectrum revealed that none of the tautomer (231) was present. Demethylcephalotaxinone has been isolated from C. harringtonia ( I l l ) , and the synthetic product was found to be identical to the natural product. However, when 113 was heated under reflux with an excess of 2,2-dimethoxypropane in methanol/ dioxan, cephalotaxinone (112) was formed and isolated in 40% yield. Finally, reduction of 112 with sodium borohydride proceeded in a stereospecific fashion to give racemic cephalotaxine (105a). An alternative route (Scheme 48) was used by Dolby et al. (160)to prepare the tricyclic enamine (225).A Vilsmejer reaction between 3,4-methylenedioxyN,N-dimethylbenzamide (232),and pyrrole gave the amide (233)in 80% yield. Reduction with sodium borohydride provided the benzyl pyrrole (234),which

1.


232

233

235

234

236

79

231

lLAH 238

SCHEME 48. Dolbj's preparation o/ enaminc2 225.

was further reduced to 235 catalytically over a rhodium-alumina catalyst. N-Acylation with chloroacetyl chloride gave 236 which on irradiation was cyclized to the tricyclic amide (237). Reduction with 1ithiu.m aluminium hydride yielded the saturated amine (238), and this was converted to the required enamine (225)by treatment with mercuric acetate. A chelating ionexchange resin was used to remove excess of mercuric acetate-a procedure superior to precipitation of the sulfide with hydrogen sulfide. Attempted annulation of 225 with ethyl x-bromoacetoacetate led to the rearranged tetracyclic compound 239 (R = C0,Et) and not to the expected product (240). Hydrolysis and decarboxylation of 239 (R = C0,Et) gave the ketone (239, R = H) which on further reduction yielded the amine (241). identical to the material prepared some years ago (161) by an independent route.

80


240

241

239

Alkylation of 225 with bromoacetone (160)gave the expected product 227, but attempts to cyclize this material gave the rearranged compound 239 (R = H) once more. It was postulated by Dolby et al. that the initially formed product was the desired compound 240 which then rearranged to the observed product 239 (R = C0,Et) by the mechanism summarized in Scheme 49. 0

I1

225

BrCH,~-C--CH,CO,El f

240

I 0

0

239 R = C0,Et

SCHEME 49. Dolby's mec~huiiisnt.fbr reurraizgeimwt of' 240

to

239.

1.

81

ER )ITHRI.VA AND RELATED ALKALOIDS

242

243 (I)

TFAA

(iil SnCI,

238

244

1

Hg(OAc1,

225

SCHEME 50. A n alternatice preparation of enaminr 225

Yet another method has been described (162)(Scheme 50) for the preparation of the tricyclic enamine (225). N-Alkylation of ethyl pyrrole-2-carboxylate with 242 in the presence of sodium hydride gave, after hydrolysis, the amino acid (243). This was cyclized to 244, reduced to 238, then oxidized to 225. Alkylation of 225 with propargyl bromide, followed by hydration with a mercuric salt gave the ketone (227), but this could not be cyclized, thus confirming the observation made by Weinreb and Auerbach (156)but contrasting with the report of Dolby et al. (160). A photochemical route to the key amine (238) has been described by Tse and Snieckus (163) (Scheme 51). The maleimide (245) was iodinated in the

245

246

241 SCHEME 5 1. A photochemical prc,parution of tricyclic amine 238

82


presence of silver trifluoroacetate at the 6-position, then treatment with methyl magnesium iodide, followed by dehydration gave 246. A 40% yield of 247 was obtained on irradiation of the alkene 246, and reduction then gave 238. The second total synthesis of cephalotaxine (157-159) was very different conceptually since it was a convergent synthesis involving the two intermediates 248 and 249. The azabicyclic intermediate (248) was prepared from pyrrolidone (250) (Scheme 52), which with the Meerwein reagent gave 251. The latter was treated with an excess of ally1 Grignard reagent to yield 252.

248

249a X = C1 249b X = I

251

250

n

254

253

Me,SiCI

Me,SiO

i

1

+H

Z 0 -

3

248

OSiMe,

L

J

255

256

SCHEME 52 Seriimelhach's synthesis of cephalota.uine

1.

ER Y T H R I N A AND RELATED ALKALOIDS

83

N-Acylation with tert-butoxycarbonyl azide to 253 was followed by oxidative ozonolysis and esterification to 254. The yield of 254 from 252 was 61% in a procedure whereby the intermediates were not isolated. The diester (254) was subjected to the acyloin condensation with a potassium-sodium alloy and the product was isolated as the O,O,N-trisilyl compound (255). This was oxidized immediately with bromine to 256 and treatment with diazomethane gave 248. The yield of 248 from 254 was 55%. Intermediates 249a and 249b were obtained from piperonal by standard methods. The essential intermediate 257 required for ring closure to the cephalotaxus skeleton was obtained (about 60% yield) by combining 248 and 249 in acetonitrile solution. A number of methods of cyclization of 257 was studied (Scheme 53). In the first approach 257a was treated with sodium triphenylmethide, when a 13-16% yield of cephalotaxinone (112) could be isolated

257a X 257b X

= C1

112

=I

7

258 SCHEME 53. The cyc1i;atiorr rcvictions t o cephalotasinone

NCOCF,

'$

*

NCOCF,

"OF,

BzO

/

\

OMe

\

BzO

OMe 26 1

260

INaOH

OMe

GMe

OMe

OMe

263

M

e

O

I

262

( I ) TFA In) CH,N,

g

/ (1)

OMe Meo$~

Pd C H,

1111 K K O ,

NCOCF,

HO

/

\

OMe BzO

\

265

OMe 264

.i

266 SCHEME 54. A hii~genriicull.vputteriicd approach to cc~phali~rurinr.

1.

E R Y T H R I X A AND RELATED ALKALOIDS

85

from the complex mixture. The reaction was presumed to involve the benzyne anion (258) as an intermediate. No improvement in yields could be gained by using the iodo compound (257b) or by variation of the conditions. The yield of 112 was raised to 35% when the anion (259) derived from 257b was treated with a Ni(0) complex to induce nucleophilic displacement of iodine. In an alternative procedure, the anion (259) was treated with a sodiumpotassium alloy to form cephalotaxinone (112) in 45% yield. However cephalotaxinone was obtained in 94% yield when 25713 was treated with potassium tert-butoxide in refluxing ammonia with simultaneous irradiation with a Hanovia 450-W medium pressure lamp. These conditions caused radical cleavage of the aromatic ring-iodine bond in the anion (259),followed by coupling of the aromatic radical with the nucleophilic center. Finally, reduction of 112 with diisobutyl aluminium hydride gave ( -t)-cephalotaxine (105a) An approach to the cephalotaxine skeleton, based upon the presumed biogenetic route, has been reported (164) and involves the oxidation of the I-phenethylisoquinoline derivative (260) with VOF, (Scheme 54). Alkaline cleavage of the dienone (261)gave 262 which, as the hydrochloride salt, was reduced 263. N-trifluoroacetylation followed by 0-methylation yielded 264 which, after hydrogenolysis to 265, was oxidized with potassium ferricyanide to give the dienone (266). 2. Esters of Cephalotaxine Although cephalotaxine itself exhibits no significant antileukemic activity, a number of naturally occurring esters of the alkaloid, the harringtonines (107-110), are active against L1210 and P388 leukemias in mice (89, 100, 108), and so some attention has been devoted to the synthesis of the dicarboxylic acid side chains (see also Section IV,A). The hydroxydicarboxylic acid (270), derived by hydrolysis of deoxyharringtonine, was synthesized by the method shown in Scheme 55 to confirm the structure deduced by spectral methods (see Section IV,A). Conventional chemistry was employed; methyl isopentyl ketone (267)was reacted with diethylcarbonate in the presence of sodium hydride to yield the ketoester (268).Addition of HCN gave 269, hydrolysis of which provided the hydroxydicarboxylic acid (270). The overall yield was 48%. Esterification with diazomethane gave the diester, which was partially hydrolyzed to the halfester (122), the most hindered ester function remaining intact. This, after conversion to the half-ester acid chloride, was used to acylate cephalotaxine. A pair of diastereomorphs was produced, neither of which proved to be identical to deoxyharringtonine. It was concluded that the latter must have structure 110 in which the ester linkage to cephalotaxine involves the tertiary,

86

S. F . DYKE AND S. N. QUESSY

0

261

268

OMe 0 %OH 122

0

123

SCHEME 55. S.vnthetic proof of structure of deoxyharringtonine.

rather than the primary carboxyl group. However, when the isomeric halfester (123) was prepared, acylation of cephalotaxine could not be achieved, presumably because of steric hindrance at the carboxyl group. An alternative synthesis of 123 (165) (Scheme 56) started from the commercially available dimethyl itaconate (271, R = Me). Epoxidation to 272 (R = Me) was achieved with trifluorperacetic acid, and this, with isobutyllithium and cuprous iodide, gave the diester (273, R = Me). The benzyl ester (273, R = CH,Ph) was prepared in a similar way from 271 (R = CH,Ph) and 272 (R = CH,Ph). Catalytic hydrogenolysis of 273 (R = CH,Ph) gave the required half-ester (123). Finally 123 was resolved with ephedrine. Auerbach et d. (165)also failed in their attempts to acylate cephalotaxine to deoxyharringtonine. However, deoxyharringtonine (110)has been synthesized (166-168) by the method summarized in Scheme 57. The lithium salt (274) of 3-methyl-lbutyne was condensed with ethyl tert-butyloxalate to give 275 which, after

1.

87

E R Y T H R I X A AND RELATED ALKALOIDS

CF,CO,H

'C0,Me 271

272

C0,Me 273 ( R = Me = 121) 273 (R = H = 123)

SCHEME 56. A n alternatioe synthesis of the acid 123.

reduction and hydrolysis, yielded the cc-ketoacid (276). Conversion of 276 to the acid chloride followed by reaction with cephalotaxine provided the ester (277). Deoxyharringtonine (110)was produced when 277 was condensed

Ll+-C-c

i i

EtO CC0,t-Bu

0 P

o=c-c-c= 1

0-t-Bu

274

275

1

(i) HJPdiC (ii) TFA

(i) SOCI, (ii) cephalotaxine

HO,C

276

"

I

/I

-c'

+

OMe 0 277

\

MeC0,Me;LDA

110

SCHEME 57. Synthesis of deoxyharringtonine

88


with the lithium salt of methyl acetate. The mixture of diastereomorphs was separated by thin layer chromatography. The hydroxyacid (118) obtained by the hydrolysis of harringtonine was synthesized (169) by the route shown in Scheme 58. Condensation of the lithium salt (278) with ethyl tert-butyloxalate gave 279, which with the lithium salt of methyl acetate was converted to 280. Hydrolysis with trifluoracetic acid yielded 281 (R = H) which with diazomethane gave the dimethyl ester (281, R = Me). Catalytic hydrogenation and hydrogenolysis with 10% palladium on carbon yielded 118 which, apart from optical rotation, was found to be identical to material obtained from harringtonine, thus confirming the structure of harringtonine deduced by spectral methods (see Section IV,A). When the half-ester (281, R = H) was treated with hydrogen over palladium on charcoal, the lactone (282)was produced. Harringtonine (107) has been synthesizcd (170) by the method shown in Scheme 59. Claisen condensation between 283 and ethyl oxalate in the presence of NaH gave 284 which, when heated under reflux with aqueous HCl, was converted to a mixture from which the oxide (285) was isolated. Without purification, 285 was treated with HCl/MeOH to yield 286, saponification of which yielded the unsaturated acid as its sodium salt 287. After conversion to the acid chloride, reaction with cephalotaxine yielded 288.

Li+-Cec

4Me,COCOCO,Et

t-Bu0,C

"--J? C=C

1

219

218

MeCO:g,LDA

OBz

OH

OBz +

t-BuOZC \CO,Me

281

280

H, Pd C EtOAc

w

0

2

M

e

&H

C0,Me C0,Me 118

282

SCHEME58. Synthetic proof o j structure of harrinytonine

1.

E R YTHRINA A N D RELATED ALKALOIDS

89

Hydration of the double bond of 288 gave 289, on which a Reformatski reaction was performed to yield harringtonine (107) together with epiharringtonine (because of the two modes of hydration of the double bond in 288) (Scheme 59). The required ester (283) was prepared by first condensing isobutyraldehyde with malonic acid to form 290, followed by isomerizing with 0 CHCH2C02Et

283

286

(CO,Et), NaH

’

I1

)

I

CHCHCC0,Et C02Et 284

285

LCO*Me 107 SCHEME 59. S?;nthesis of harringronine

90


base to 291 and then by esterifying to 283. A very similar route to harringtonine has been described by Chinese workers (171).

: i-x CHO

CH=CHCO,H 290

1 -

283

BF, EtOH

KOH H,O

>,:HCH2COzH 29 1

In the structural analysis of isoharringtonine (109),the relative configuration of the diacid side chain was solved (172) by a synthesis (Scheme 60).

_j____l_

C0,Et COMe

-!(LL!?KOH %,

WCozH

292

/ *o

293

H

C0,Me

d%C02Me =5 . 8 5 3

CO,H

C0,Me

0 294

H? 6 = 6.8 295

297

I

OSO, H,O,

.."..x

0 5 0 ,

0,Me

, C0,Me OH

296

I

MeO,C&H OH 298

SCHEME 60. Relatiue configuration of side chain of i.so/zarringtorzine.

H,O,

1.

ERYTHRI,VA AND RELATED ALKALOIDS

91

Trans-esterification of the alkaloid with sodium methoxide gave a single dimethyl ester which possessed either the threo (298) or the erythro configuration (296). Ethyl isoamylacetoacetate (292) was converted to 293 by a method developed by Vaughn and Anderson (173). Esterification of 293 gave the trans-dimethyl ester (297) which, with osmium tetroxide and hydrogen peroxide, yielded the single diol (298). This was assigned the threo configuration, in view of the known cis-hydroxylation achieved by osmium tetroxide. In an alternative sequence, the diacid (293)was dehydrated with P,O, to the anhydride (294), which in turn was esterified to the cisdiester (295). The vinyl proton absorption at 6 5.85 for 295 compares with the value of 6 6.8 for the trans structure (297). Cis-hydroxylation of the cis-diester (295) yielded the erythro compound (296). The PMR spectrum of 296 was found to be identical with that of the diol diester derived from isoharringtonine. The absolute configuration of the side chain of isoharringtonine has been deduced (174)to be 2R,3S(299)by comparing the C D spectra of its molybdate complexes with those of piscidic acid (300)of known absolute configuration.

COzH

CO,H

299

300

An alternative synthesis of 295 involves (175)the addition of diisoamyllithium cuprate to dimethylacetylene dicarboxylate. The major product (89%) was the required 295 together with some 297. The mixture was separated by chromatography.

VII. Pharmacology Many Erythrina alkaloids possess curare-like action. Alkaloidal extracts from different parts of Erythrina species have been used in indigenous medicine, particularly in India ( 176).Many pharmacological effects, including astringent, sedative, hypotensive, neuromuscular blocking, CNS depressant, laxative, and diuretic properties, have been recorded for total alkaloid extracts, although not all these properties can be associated with the erythrinane structure alone (38, 177, I78). A few purified Erythrina alkaloids have been shown to have useful pharmacological properties. Cocculine (56) and cocculidine (54) nitrates have been

92


reported to show hypotensive action in dogs, due mainly to ganglionic blocking action. Neither alkaloid had a significant effect on the CNS (179). Isococculidine (37)was shown to be a weak blocking agent at the cholinergic receptor in frogs (180).The juice of the leaf and bark of E. suberosa Roxb. was reported to have antitumor activity and the major alkaloid isolated was erysotrine (1)(181).Erysotrine was found to exhibit properties consistent with those of a competitive neuromuscular blocking agent in anaesthetized dogs (182). Cocculolidine (61) was reported to be an insecticidal alkaloid (76). Analogs of Erythrina alkaloids that lack the aromatic ring have been prepared for structure-activity studies (183). Antitumor activity in P388 and L1210 experimental leukemia systems was detected in extracts from the seeds of C. harringtonia K. Koch var. harringtonia (8,95).It was soon discovered that the major component, cephalotaxine (105a), was inactive and that the activity resided in the esters 107-110 (the harringtonines) ( 184187). Harringtonine (107) and homoharringtonine (108) had about the same activity in the P388 system and both were more active than deoxyharringtonine (110) and isoharringtonine (109).The latter two were only marginally active in the L1210 system (8).The optimum dose (for mice) was in the range 2-12 mg/kg by intraperitoneal injection over a period of 9 days (186, 187). Harringtonine appears to be the most effective agent and recent studies in the People’s Republic of China have shown that it is effective against L615 leukemia, L7212 leukemia, sarcoma 180, and Walker carcinosarcoma 256 (188).Harringtonine also appeared to be effective in the treatment of acute and chronic myelocytic leukemia in humans (189). The mode of action of the harringtonines has been investigated. All inhibit protein synthesis in eukaryotic cells (190-192). The principal effect of harringtonine was inhibition of protein biosynthesis in HeLa cells (193). Homoharringtonine, a potential antineoplastic alkaloid ( 194, was cytotoxic in HeLa, KB, and L cells growing in monolayer cell cultures (194). In view of the difficulty in obtaining a sufficient supply of the active esters for biological screening, considerable effort has been applied to the problem of preparing the esters from the more readily available cephalotaxine (105a) (see Section V1,C). This effort has also resulted in the preparation of many analogs containing ester groups that do not occur in the natural alkaloids and that have been used to obtain structure-activity relationships (168, 171, 195). Although some degree of structural variation must be tolerated, since homo-, iso-, and deoxyharringtonine show activity, most of the synthetic esters were found to be inactive (195).From a large number of cephalotaxine esters, the only synthetic ones to show significant activity in the P388 systems are those having the side-chain structures 301-304 (196).There appears to be little rationality in the structure-activity relationship.

1.

E R Y T H R l N A AND RELATED ALKALOIDS

93

OCH, 301 R = COC(=CH,)CH,CO,Me 302 R = COCH=CHCO,Me(trans) 303 R

=

H ,,,, ,OCO,CH2CC1, CO-C, Ph

304 R = CO2CH2CCI3

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CHAPTER2-

THE CHEMISTRY OF C... DITERPENOID ALKALOIDS S . WILLIAM PELLETIER AND NARESH V . MODY Institute f o r Naturul Products Research and Department of Chemistry. University of Georgia. Athens. Georgia

I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............ I1. Vedtchine-Type Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . A . Veatchine and Garryine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B. Garryfoline, Ovatine, and Lindheimerine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Cuauchichicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D . Garryfoline-Cuauchichicine Rearrangement . . . . . . . . . . . . . . . . . . . . . . . . . . . E . Napelline (Luciculine), Isopapelline, Lucidusculine, and 12-Acetylnapelline F. Songorine (Napellonine or Shimoburo Base I), Norsongorine, Songorine N-Oxide, and Songoramine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . G. Anopterine, Anopterimine, Anopterimine N-Oxide, Hydroxyanopterine, and Dihydroxydnopterine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I11. Atisine-Type Alkaloids . . . . . . . . . ..... ....... A . Atisine and Isoatisine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . B . Dihydroatisine and Atidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C . Ajaconine and Dihydroajaconine . . . . . . . . . . . . . . . . . . . ........... D . Kobusine and Pseudokobusine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . E . Ignavine and Anhydroignavinol ............................. F . Hypognavine and Hypognavin ...................... G . Isohypognavine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . H . Denudatine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......... I . Vakognavine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . J . Hetisine (Delatine) and Hetisinone . . . . . . K . Hetidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . L . Miyaconitine and Miyaconitinone ............................. M . Delnudine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . N . Spiradine A, Spiradine B, and Spiradine C . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0. Spiradine D and Spiredine . . . . . . . . . . . . ........ ......... P . Spiradine F and Spiradine G . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Q . Spireine . . . . . . . . . .......................................... IV . Bisditerpenoid Alkaloids . . . . . . . . . . . . . . . . . . . . . . A . Staphisine and Staphidine . . . . . . . . . . . . . . . . B . Staphinine and Staphimine . . . . . . . . . . . . . . . . ................... C . Staphigine and Staphirine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . D . Staphisagnine and Staphisagrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . V . Behavior and Formation of the Carbinolamine Ether Linkage in Diterpenoid Alkaloids: The Baldwin Cyclization Rules. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . lr1. "C-NMR Spzctroszopy of C,,- Diterpenoid Alkaloida. . . . . . . . . . . . . . VII . Mass Spectral Analysis of C,,- Diterpenoid Alkaloids . . . . . . . . . . . . . . . . . . . . . .

100 102 102 104 106 109 112

114 116 122 122 124 124 125 128 129 130 131 1-32 133 135 136 138 139 140 142 143 144 144 146 147 148 149 160 163

THE ALKALOIDS. VOL. X V I l l Copyright @ 1981 by Academic Press. Inc. All rights of reproduction in any farm reserved. ISBN 0 12 469518 3

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S . WILLIAM PELLETIER AND NARESH V. MODY

VIII. Synthetic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . A. Total Synthesis of Optically Active Veatchine. . . . . . . . . . . . . . . . . . . . . . . . . . B. Total Synthesis of Napelline . . . . . . . . . . . . . . . . . C. Construction of the Denudatine Skeleton. . . . . . D. A Synthetic Approach to Ajaconine and Atidine.. . . . . . . . . . . . . . . . . . . . . . . E. Intermediates for the Veatchine- and Atisine-Type Alkaloids. . . . . . F. Construction, Degradation. and Selective Reduction of the Oxazolidine Ring of C,,-Diterpenoid Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IX. A Catalog of C,,-D kaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . ........................................

168 I68

179

194 196 211

I. Introduction The diterpenoid alkaloids, isolated mainly from Aconitum and Delphinium species (Ranunculaceae), have been of great interest since the early 1800s because of their pharmacological properties. Extracts of Aconitum species were used in ancient times for treatment of gout, hypertension, neuralgia, rheumatism, and even toothache. Extracts have also been used as arrow poisons. Some Delphinium species are extremely toxic and constitute a serious threat to livestock in the western United States and Canada. Delphinium extractsalso manifest insecticidal properties. In the last 30 to 40 years, interest in the diterpenoid alkaloids has increased because of the complex structures and interesting chemistry involved. The diterpenoid alkaloids may be divided into two broad categories : those based on a hexacyclic C,,-skeleton and those based on a C,,-skeleton. The highly toxic C, ,-diterpenoid alkaloids, commonly known as aconitines, have been reviewed ( I ) in Volume XVII of this treatise. The C,,-diterpenoid alkaloids contain three basic skeletons : Atisine-type (i), Veatchine-type (ii), and Delnudine-type (iii). The atisine skeleton incorporates an ent-atisane nucleus and does not obey the isoprene rule. The veatchine skeleton, which occurs in the Garrya alkaloids, is modeled on an ent-kaurane nucleus and obeys the isoprene rule. It differs from the atisine skeleton in that ring D is five- rather than six-membered. Biogenetically, these alkaloids are probably derived from tetracyclic or pentacyclic diterpenes in which the nitrogen atom of methylamine, ethylamine, or P-aminoethanol is linked to C-19 and C-20 in the diterpenoid skeleton to form a substituted piperidine ring. There have been no detailed biogenetic studies on these alkaloids. The delnudine skeleton is an interesting curiosity in that it is difficult to explain how delnudine is derived from an atisine skeleton or from a pimaric acid skeleton. Recently, a new class of diterpenoid alkaloids, known as bisditerpenoid alkaloids, has been isolated from the seeds of Delphinium staphisagria (2). The bisditerpenoid alkaloids (e.g., staphisine, iv) may be formally derived by

2.

THE CHEMISTRY OF C20-DITERPENOID ALKALOIDS

( i ) Atisine skeleton

101

(ii) Veatchine skeleton

(iii) Delnudine

attachment of two different molecules of C,,-diterpenoid alkaloids at the C-16 position. y

3

19./N\,20. H3FyJ2'

6'

\

10'

H,C--

(iv) Stdphisine

The numbering system for the alkaloids with the basic atisine (i), veatchine (ii), and delnudine (iii) skeletons used in this chapter is in accord with proposals initiated by Dr. J. w. Rowe and cosponsored by the author (3). The earlier work on the chemistry of C20-diterpenoid alkaloids has been reviewed in Volumes IV(4), VII(5), and XIl(6) of this treatise, in books on

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S. WILLIAM PELLETIER AND NARESH V. MODY

alkaloids by Boit (7) and Pelletier (8),in The Alkaloids, Specialist Periodical Reports (9-11) and in other reviews (12-18). This chapter deals with the chemistry of C,,-diterpenoid alkaloids reported in the literature available to us since the last review in Volume XI1 of this treatise, as well as certain unpublished works from our institute. Included in this chapter is a catalog of ali known C,,-diterpenoid alkaloids showing the correct structures, physical properties, plant sources, and key references. Previously published books (19-21) and recent reviews (15-16) have reported incorrect structures for several well-known C,,-diterpenoid alkaloids. This catalog should be very useful for it presents in a single place important structural information on the C,,-diterpenoid alkaloids that has been scattered through hundreds of papers and dozens of review articles.

11. Veatchine-Type Alkaloids The veatchine-type alkaloids are also known as the Garrya alkaloids because they were first isolated from Garrya species. In 1946, Oneto reported (22)the isolation of two isomeric crystalline alkaloids, veatchine and garryine, from the bark of Garrya veatchii Kellogg. Later, Karel Wiesner and co-workers at New Brunswick initiated work on the structure elucidation of veatchine and garryine and pointed out the striking similarity between the chemistry of atisine and veatchine. They elucidated the structures of veatchine and garryine, and their results greatly assisted progress in the structure elucidation of both veatchine- and atisine-type alkaloids. Since structures of the veatchine-type alkaloids were first to be completed, their chemistry will be reviewed first.

A. VEATCHINE AND GARRYINE Veatchine, the major alkaloid of G. veatcliii Kellogg, is a strong tertiary base (pK, 11S)that undergoes a facile isomerization of the oxazolidine ring to garryine (pK, 8.7) by treatment with base or even by simple refluxing in methanol. Veatchine forms the ternary immonium salt known as veatchinium chloride by treatment with hydrochloric acid and may be regenerated from veatchinium chloride by treatment with cold base. On the basis of chemical and degradation studies, Wiesner and co-workers elegantly established (23, 24) the structures of veatchine and garryine as l b and 2, respectively. Early work on the chemistry of veatchine and garryine has been reviewed by Wiesner and Valenta (12),and later by Pelletier and Keith (6,8). The stereochemistry of the normal-type oxazolidine ring in veatchine, atisine, and other related alkaloids was ill-defined in the literature (2j),

2.

THE CHEMISTRY OF Czo-DITERPENOID ALKALOIDS

103

for example, the P-configuration was assigned to the C-20 proton in veatchine (lb) and related alkaloids without any evidence (26). Recently, Pelletier and Mody reported (27,28) unusual findings about the conformation of the oxazolidine ring of veatchine and related alkaloids by 13C-NMR spectroscopy. The I3C-NMR spectrum of veatchine shows two sets of signals for the oxazolidine ring and the piperidine ring carbons in CDCl, solution at room temperature. On the basis of this unusual observation they concluded that veatchine exists as a mixture of C-20 epimers ( l a major and l b minor) in solution. When veatchine is regenerated from veatchinium chloride (3), in which C-20 is trigonal, by treatment with base, formation of the oxazolidine ring takes place from both sides of the trigonal C-20 carbon to give epimers l a and lb.

lb

2 Garryine

la

1 Veatchine

3 Vedtchinium chloride

These findings were confirmed (29,30)by demonstrating the coexistence of C-20 epimers in the same crystal of veatchine by a single-crystal X-ray analysis. Crystallization of two epimers in a disordered relationship is a highly unusual observation. Even though veatchine exists as a mixture of

104

S. WILLIAM PELLETIER AND NARESH

V.

MODY

epimers, separation of these epimers would be extremely difficult because veatchine is not particularly stable in hydroxylic solvents such as methanol (see Section V). Because of the inconvenience of presenting two structures each time veatchine is referred to, structure 1 will be used to represent both epimers l a and l b .

4 Atisine

5 Atisinium chloride

Veatchine has been chemically related to atisine (4) by conversion to a common intermediate (34,and the absolute configuration of atisine has been established by a single-crystal X-ray analysis of atisinium chloride (30) (5). Therefore, the absolute configuration of veatchine is assigned as 4S, 5S, 8R, 9S, 10R, 13R, 15R, and 20SR. The designation of the absolute configuration of C-20 as “SR” was chosen to indicate that, in any given sample of veatchine, both epimers exist and that the 20s (ex0 configuration of the oxazolidine ring) epimer predominates. The 3C-NMR spectrum of garryine (2)exhibits (28)only one set of signals for the oxazolidine ring carbons, the piperidine ring carbons, and the C-4 methyl group, a fact which indicates that garryine does not exist as a pair of C-19 epimers. During recent work on the isolation of veatchine from the bark of G. veatchii (32), the presence of garryine was not detected. This observation suggests that veatchine may have isomerized to garryine during the earlier isolation work and that garryine may be an artifact.

B. GARRYFOLINE, OVATINE, AND LINDHEIMERINE Ovatine (6) and lindheimerine (7) have been isolated (33)for the first time from the bark and leaves of G. ocata var. lindheimeri Torr., a plant that has shown confirmed antitumor activity in vivo. These two new alkaloids are accompanied by the known alkaloid, garryfoline (S), which also occurs in the Mexican tree, G. laurifolia Hartw (34). The structure of the major alkaloid, ovatine (6),was assigned on the basis of ‘H- and 13C-NMR data of ovatine and garryfoline and was confirmed by conversion of ovatine to garryfoline and vice versa. The ‘H-NMR data of ovatine revealed the presence of two different sets of signals for the C-4

2.


105

methyl group and the C-20 proton in a 1 :3 ratio and one set of signals for an aceloxy group, the N-CH,-C group, and the exocyclic double bond. The 13C-NMR spectrum of ovatine in CDCl, at room temperature also exhibited the presence of two different sets of signals for the oxazolidine ring F, the piperidine ring E, the C-4 methyl group, and certain other carbon atoms. Comparison of the 'H- and 13C-NMR spectra of ovatine with those of garryfoline revealed that the only difference between these alkaloids was the presence of an acetoxyl group at C-15. Each of these alkaloids exists as a mixture of C-20 epimers in solution. It is worth noting that in the structure assigned to garryfoline (6B) (25,26),a P-configuration was assumed without evidence for the C-20 hydrogen.

6 R = Ac Ovatine 8 R = H Garryfoline

6a R = Ac 8a R = H

9

7 Lindheimerine

6b R = AC 8b R = H

10

Mild hydrolysis of ovatine at room temperature gave the known alkaloid garryfoline, a fact which indicates that the acetoxyl group is present at C-15 in ovatine. Garryfoline afforded the unusual immonium salt (9) instead of ovatine on treatment with acetic anhydride and pyridine at room temperature. Treatment of ovatine with acetic anhydride and pyridine also gave 9

106

S. WILLIAM PELLETIER AND NARESH V . MODY

in quantitative yield. Garryfoline was converted to ovatine via lindheimerine (7) in two steps. Refluxing 9 in chloroform yielded lindheimerine (7) in 90% yield. Treatment of 7 with ethylene oxide in acetic acid gave ovatine in almost quantitative yield. Thus, the structures of ovatine and garryfoline can be represented as an epimeric mixture at C-20 of 6a and 6b for ovatine and 8a and 8b for garryfoline, with the a epimer predominating. Structure 7 was assigned to the minor alkaloid, lindheimerine, from spectral data. The ‘H- and I3C-NMR spectra revealed the presence of one acetoxyl group, a C-4 methyl group, an exocyclic double bond, and a C-20 imine group on a veatchine-type skeleton. Comparison of the 13C-NMR spectrum of lindheimerine with that of veatchine azomethine acetate (10) gave evidence for the presence of the C-15 6-acetoxyl group in lindheimerine. The structure of lindheimerine (7)was confirmed by comparison with the degradation product of compound 9, which was identical with lindheimerine. Lindheimerine occurs in extremely small quantity by comparison with ovatine. Since these two alkaloids are closely related chemically, we suggest that lindheimerine may be a biogenetic precursor of ovatine. These alkaloids did not exhibit any antitumor activity in uiuo or in uitro. C. CUAUCHICHICINE During investigation of the constituents of G . ouatu var. lindheimeri, two well-known alkaloids, garryfoline (8) and cauchichicine, as well as ovatine and lindheimerine, were isolated (33); Djerassi and co-workers (25, 34) had previously isolated the former alkaloids from the Mexican tree, G. luurifoliu, and established their gross structures. Treatment of garryfoline with dilute hydrochloric acid at room temperature results in rapid isomerization to cuauchichicine. The latter was assigned structure 11 by Vorbrueggen and Djerassi in 1962 (25,35).They assigned the a-configuration for the C-16 methyl group in cuauchichicine on the basis of chemical correlation of cuauchichicine azomethine (12) with ( dihydrokaurene (13). The structure of the latter, a minor hydrogenation product of ent-kaurene (14),was based on the behavior of ent-kaurene during catalytic hydrogenation. A a-configuration was assigned for the C-20 hydrogen in cuauchichicine without any evidence. Recently, Pelletier and co-workers (36) revised the structure of cuauchichicine to 15 on the basis of I3C-NMR spectral analysis and X-ray crystallography. A 3C-NMR study of cuauchichicine indicated that it exists as a single C-20 epimer unlike other normal-type oxazolidine ring-containing diterpenoid alkaloids such as veatchine, ovatine, garryfoline, and atisine. An a-configuration was assigned to the C-20 hydrogen on the basis of comparison of the I3C-NMR spectrum of cuauchichicine with those of veatchine and

)-“a”-

2.

THE CHEMISTRY OF C~O-DITERPENOIDALKALOIDS

11

107

12

I c

c

13 “p”-Dihydrokaurene 4%

I

H,. NI

14 ent-Kaurene

18 “r”-Dihydrokaurene

atisine. To establish the stereochemistry of the C-16 methyl group in cuauchichicine by I3C-NMR spectral analysis, a pair of stable C-16 epimers was prepared. Cuauchichicine was heated at reflux in methanol to afford isocuauchichicine (16) in quantitative yield. During this rearrangement the C-16 methyl group did not epimerize. Heating of cuauchichicine o r isocuauchichicine in a methanolic solution of 2% sodium hydroxide at reflux gave a mixture of (2-16 methyl epimers of isocuauchichicine. These epimers were separated by chromatography over alumina using hexane and benzene as the eluting system to yield pure samples of isocuauchichicine (16) and epiisocuauchichicine (17).Comparison of molecular models of 16 and its epimer 17 revealed that the methyl group at C-16 is partially crowded in the pposition in contrast to the @-position.Steric compression would be expected to cause the p-methyl group to appear at higher field in the I3C-NMR spectrum than the r-methyl group. Accordingly, the signal a t 10.1 ppm was assigned to the p-methyl group in 16, and the signal at 15.9 ppm was assigned

108


15 Cuauchichicine

19

13a R = CH,OH 13b R = CHO 13c R = CH, “8”-Dihydrokaurene

2.

THE CHEMISTRY OF C ~ O- DI T E R P EN O I DALKALOIDS

109

to the sc-methyl group in 17. These results afforded evidence for the presence of the 8-methyl group at C-16 in cuauchichicine (10.1 ppm) and therefore structure 15 was assigned to cuauchichicine. Subsequently, this structure was confirmed by a single-crystal X-ray analysis of cuauchichicine (36). The incorrect structure 11 originally assigned to cuauchichicine requires that either the structure of the final degradation product, ( - )-“P”-dihydrokaurene (13), is incorrect or that the C-16 methyl group must have epimerized somewhere in the six-step correlation sequence. Because the structural assignments of more than 100 natural products depend on ( -)-“P”-dihydrokaurene, the structure of this important diterpene was reinvestigated. Catalytic hydrogenation of ent-kaurene (14) afforded a mixture of ent-kauranes consisting mainly of ( - )-“a”-dihydrokaurene. The ‘‘P’-epimer was produced in too small a yield to permit its isolation in a pure state. X-ray crystallography of ( -)-“a”-dihydrokaurene demonstrated the structure to be 18. Therefore, the structure previously assigned for ( - )-“P”-dihydrokaurene (13) is correct. These results indicate that epimerization of the C-16 methyl group must have taken place during degradation of cuauchichicine to (-)“P”-dihydrokaurene. This unanticipated epimerization most likely occurred during Wolff-Kishner reduction of the intermediate ketone 19 and accounts for the error in the assignment of configuration of the C-16 methyl group in cuauchichicine. The absolute configuration of cuauchichicine was determined as 4.9, 5S, 8R,10R, 16R, and 20s. It is worth noting that cuauchichicine is the first normal-type oxazolidine ring-containing alkaloid that does not exist as a pair of epimers at C-20, either in solution or in the solid state.

D. GARRYFOLINE-CUAUCHICHICINE REARRANGEMENT In 1955, Djerassi and co-workers reported (34) that the treatment of garryfoline (8) with dilute mineral acid at room temperature results in rapid isomerization to cuauchichicine (15). A similar rearrangement has been also observed in atisine, kobusine, napelline, and other terpenoids containing a methylene group at C-16 and a C-15 P-hydroxyl group. In contrast to the facile rearrangement of garryfoline, the C-15 epimer, veatchine (1), is stable even when heated in dilute hydrochloric acid. To explain the striking difference in the behavior of these two epimers toward acid treatment, a nonclassical structure for the intermediate carbonium ion has been suggested (12). Barnes and MacMillan reported (37)an investigation of this rearrangement using the epimeric (-)-kaur-16-en-l5-01~ as models. The 158-01 (20) rearranged rapidly to 16-(-)-kaur-l5-one (21) in mineral acid at room temperature whereas the 15a-01(22)was stable under these conditions. The English workers proposed a 15 + 16 hydride-shift mechanism on the basis of the

110


20 R = H 23 R = D

21 R = H

22

24 R = D

rearrangement of [15-~]-(-)-kaur-l6-en-15P-ol (23) to (16R)-[16-~]-(-)kaur-15-one (24) in hydrochloric acid. Later work by the same group, however, demonstrated (38)that compound 24 exchanges deuterium at C-16 with hydrogen in dilute acid with complete retention of configuration to give 21. Pelletier, Desai, and Mody prepared (39)several deuterated derivatives of garryfoline and cuauchichicine and studied the mechanism by I3C-NMR spectroscopy. Deuterated (C- 15) dihydrogarryfoline diacetate (26) was prepared from veatchinone (25) in three steps. Compound 26 in 10% HCl at

25

28

26 R' 27 R'

= OAc; R 2 = D = D; RL = OAc

Major Minor

31

D'

32

29

30

SCHEME 1

33

112


room temperature rearranged to 28, a compound which showed no deuterium incorporation at C-16 on the basis of 13C-NMR spectral analysis. These results indicated that the C-15 deuterium did not shift to C-16 during the rearrangement and therefore the garryfoline-cuauchichicine rearrangement does not take place via a 15 -+ 16 hydride-shift mechanism. Treatment of isogarryfoline (29) with 10% DCI in D,O at room temperature followed by treatment with base, afforded deuterated isocuauchichicine (30) in quantitative yield. Analysis of the I3C-NMRspectrum of 30 revealed the presence of deuterium at C-16 and C-17. In dilute hydrochloric acid no exchange of deuterium by hydrogen in compound 30 was detected in 24 hr, but after 96 hr, exchange was observed to give compound 31. On the basis of these results, the mechanism outlined in Scheme 1 was suggested. The mechanism involving the enol accounts for incorporation of deuterium at C-16 and C-17 and also explains the C-16 a-D, /3-CH2D stereochemistry observed. During ketonization of the enol 32, transfer of D + would be expected to occur from the less-hindered exo side of the molecule to give compound 33 containing the C-16 a-D and C-16 P-CH,D groups. These results demonstrated (39) that a 15 + 16 hydride shift is not involved but rather a mechanism involving formation of an enol followed by exopro tonation.

E. NAPELLINE (LUCICULINE), ISONAPELLINE, LUCIDUSCULINE, AND 12-ACETYLNAPELLINE Napelline (34) was isolated by Freudenberg and Roger (40) in 1937 from the poisonous roots of Aconitum napellus L. Recently, napelline has been isolated (41) from the tubers and roots of A . karakolicum, which were collected in the Terskei Ala-Tau ranges of the Kirghiz S.S.R. Early work on the chemistry of napelline has been reviewed by Wiesner and Valenta (12)and later by Pelletier and Keith (6).On the basis of extensive chemical work (42-47) and X-ray analysis (48, 49) of lucidusculine (35), structure 34 was assigned to napelline. Recently, Wiesner and co-workers OH

34 Napelline

OH

35 Lucidusculine

2.

THE CHEMISTRY OF C2o-DITERPENOID ALKALOIDS

36

113

37 Isonapelline

reported an elegant total synthesis of napelline and thus confirmed its structure. The synthesis of napelline is discussed in Section VII1,B. Treatment of napelline with dilute mineral acid results in rapid isomerization to isonapelline (42,43). The structure of isonapelline was represented as 36 with undetermined stereochemistry at C- 16. Recently, we established the stereochemistry of the C-16 methyl group in the related alkaloid, cuauchichicine, an acid-catalyzed rearrangement product of garryfoline. By analogy, the acid-catalyzed rearrangement of napelline to isonapelline should result in a C-16 P-methyl group in isonapelline. Thus structure 37 can be assigned to isonapelline. Lucidusculine was first isolated in 1931 by Japanese chemists (50, 51) from the roots of A . lucidusculurn Nakai, which is also known as A . yesoense var. Structural work on this alkaloid was carried out by Suginome and co-workers (52-57) from 1950to 1961.The structure of lucidusculine (35)was established in 1965 by a Japanese group by X-ray crystal analysis of its hydriodide (48, 49). Basic hydrolysis of lucidusculine afforded the parent alkamine known as luciculine. The latter was found to be the same as napelline. The X-ray crystal structure of lucidusculine provided a basic foundation for elucidating the structures of related alkaloids, e.g., napelline, songorine, songoramine. The chemistry of lucidusculine has been reviewed in detail earlier by Stern ( 4 , 5 ) and later in Volume XI1 of this treatise (6). 12-Acetylnapelline has been isolated by Soviet chemists (58, 59) from the epigeal parts of A . karakolicum collected in the upper reaches of the R. Tyup (Kirghiz S.S.R.) during the budding period. Chemical transformations and mass spectral analyses of 12-acetylnapelline and its derivatives have led to the assignment of structure 38. Alkaline hydrolysis of 12-acetylnapelline (38) yielded an amino alcohol identical to napelline (34). This result indicated that the new alkaloid was napelline monoacetate. Treatment of 12-acetylnapelline with acetic anhydride and pyridine gave the triacetate 39. The latter was selectively hydrolyzed by alkali to afford l-acetylnapelline (40). Oxidation of 38 with silver oxide yielded dehydro derivative 41, a result that revealed the presence of an ahydroxy group at C-1 in 38. Hydrogenation of 12-acetylnapelline over a

114

S. WILLIAM PELLETIER A N D NARESH V. MODY

OR

0Ac

38 12-Acetylnapelline

39 R = AC 40 R = H

0Ac

OAc

41

42

platinum catalyst afforded dihydroacetylnapelline (42). Formation of isoacetylnapelline (43)from 38 indicated that the hydroxy group at C-15 is not acetylated. On the basis of these chemical transformations, structure 38 was assigned to 12-acetylnapelline. In the earlier papers (58, 59) on the structure of 12-acetylnapelline, the choice between attachment of the acetyl group at position 12 or 15 was made on the basis of the mass spectral data of 12-acetylnapelline, l-acetylnapelline, and triacetylnapelline. The detailed mass spectral analysis of 12-acetylnapelline and its derivatives is discussed in Section VII.

F. SONGORINE (NAPELLONINE OR SHIMOBURO BASEI), NORSONGORINE, SONGORINE N-OXIDE, AND SONGORAMINE Songorine (44)was isolated as the major alkaloid of A . soongoricum Stapf by Yunsov (60) in 1948. This alkaloid was also found (61) in a Japanese Aconitum variety ( A . japonicum var.) and was provisionally named “Shimoburo Base 1.” Recently, Soviet workers reported the occurrence of songorine in the epigeal parts and tubers of A. karakolicurn (41,59, 58, 62) and the roots of A . monticola (63).The structure of songorine was intensively investigated by Canadian (42, 43), Japanese (46, 47), and Soviet (44, 45, 60, 64) groups between 1950 and 1960. Finally, in 1961, Sugasawa (47)proposed the correct structure of songorine. Later, in 1965, the structure of songorine (44) was confirmed (48)by direct comparison of its lithium aluminum hydride

2.

115


reduction product with napelline (34).The chemical work on songorine has been reviewed in detail by Pelletier and Keith (6) in Volume XI1 of this treatise.

CH,

OH 43

&CH2 H... -.N

,,

44 Songorine

- -H

..

OH ‘

CH,

C H -..-.-N oY&CH2 \ ;‘ ,^. ~ . \ \

2

,

5

’

45 Norsongorine

- -H

OH CH,

46 Songorine N-oxide

In 1974, Soviet researchers reported (63)the isolation of “norsongorine” (45), a known derivative of songorine, from the roots of A . monticolu. No physical properies or spectral data for norsongorine were reported by the authors. Recently, songorine N-oxide (46) has been isolated (65)for the first time from A . monticola collected in the Dzhungarian Ala-Tau on the Kuyandysai River. The structure of songorine N-oxide was elucidated from the ‘H-NMR and mass spectral data and on the basis of reduction of 46 to songorine (44) by zinc and 10% hydrochloric acid at room temperature. In 1970, Yunusov and co-workers reported (62)the isolation and structure elucidation of a new alkaloid, songoramine (47), from the tubers of A . karakolicum, collected in the upper reaches of the Tyup River (Terskei Ala-

,&CH2 , .T.. ,, , C H .+---.N I

2

5 ,

,

.

,

,

4..:.:

- -H OH

CH3

47 Songoramine

&

C2 H 5 ... ..N ”

*, . ,,~ .

CH,

48

,’

‘H

--H OH

H3

116


49 R = AC 50 R = H

Tau range). Occurrence of the same alkaloid was also reported earlier in the roots of A . soongoricum Stapf (66,67). The structure of songoramine was established on the basis of mass spectral analyses and conversion to songorint: (44).The spectral and chemical properties of songoramine are very similar to those of songorine. Hydrogenation of songoramine over platinum yielded a tetrahydro derivative (48), which proved to be identical to dihydrosongorine. Acetylation of 47 with acetic anhydride and pyridine gave an unusual immonium salt (49). Treatment of songoramine with hydrochloric acid also gave a quaternary immonium salt (SO). Thus, the presence of a carbinolamine ether in 47 was demonstrated by reductive opening and immonium salt formation. Finally, oxidation of songorine with silver oxide afforded songoramine, which confirmed its structure. The mass spectral data of songoramine, songorine, dihydrosongorine, and their acetate derivatives were analyzed. These results are discussed in Section VII.

G. ANOPTERINE, ANOPTERIMINE, ANOPTERIMINE N-OXIDE, A N D DIHYDROXYANOPTERINE HYDROXYANOPTERINE, Anopterine (Sl),the major alkaloid of the leaf and bark of Anopterus macleayanus F. Meull and bark of A . glandulosus Labill., has been isolated (68,69) by Lamberton and co-workers. Crude extracts of both Anopterus species have shown some preliminary antitumor activity in a number of test systems. The structures of anopterine and its hydrolysis product, anopteryl alcohol (S2), were assigned on the basis of a single-crystal X-ray analysis (68) of the azomethine iodide (53). The latter was formed on treatment of tetraacetylanopteryl alcohol (54) with methyl iodide in acetone after several weeks. Anopterine fails to form salts with mineral acids and simple organic acids because one of the C-2 and C-5 hydroxyl groups is strongly hydrogen bonded to the nitrogen. In order to confirm that no other change apart from the formation of the C-19 imine bond had occurred during the transformation of the tetraacetate

2.

THE CHEMISTRY OF C ~ ~ - D I T E R P E N O IALKALOIDS D

H3 7 H A ,

,c=c

p

H 2H. ?HO.. ;:- '

3

H,C------N '

,CH3

0-CO-c=c,

OR

'H

co-0..

117

OH

CH,OH 51 Anopterine

52 R = H 54 R = AC

OAc

53

54 to the azomethine iodide 53, the conversion of the azomethine iodide to anopteryl alcohol was attempted. Reaction of the azomethine iodide with aqueous ammonia or sodium bicarbonate yielded the C-19 epimers (5: 1) of compound 55. Alkaline hydrolysis of 55 gave a major product containing the carbinolamine ether linkage having either structure 56 or 57. Interestingly, the hydrolysis product (56 or 57) of compound 55 can not be reduced to anopteryl alcohol by treatment with sodium borohydride. On acetylation with acetic anhydride and pyridine followed by the usual work-up, the carbinolamine ether (56 or 57) gave back the epimeric alcohol 55. However, reduction of the azomethine iodide (53) with cold sodium borohydride gave tetraacetylanopteryl alcohol (54). The latter on alkaline hydrolysis afforded anopteryl alcohol in good yield. Thus, conversion of 53 to anopteryl alcohol

55

56

118


V.

MODY

(52) confirmed that no skeletal rearrangement had occurred other than the formation of an imine bond during the transformation of 54 to 53. These results also confirmed the structure of anopteryl alcohol and its tetraacetate.

::;,5:--CH2 OH

H,C------N HO..

'~

OH

CH,;

\--

.....0

57

H O . @CH2 ~

,

-,

-. . ......

H C... ..N

AcO.. @CH2 ,

9, --- --

H,C------N

OH

,

... .......

2

CH,

CH, O A c

58

59

Oxidation of anopteryl alcohol with alkaline potassium ferricyanide yielded the carbinolamine ether (56 or 57) as a minor product (8%) and compound 58 as the major product. The structure of 58 was elucidated by an X-ray crystal analysis. Compound 58 was isolated from the oxidation reaction mixture only after acetylating the mixture, from which the carbinolamine ether was first removed, and then hydrolyzing the acetylated product. Acetylation of compound 58 gave triacetyl derivative 59, in which the epoxide ring was opened. Treatment of anopteryl alcohol with acetic anhydride and pyridine at 100" for 4 hr or longer gave tetraacetylanopteryl alcohol (54) in high yield. Less drastic acetylation conditions gave a mixture of compound 54, triacetyl derivatives 60 and 61, and diacetylanopteryl alcohol 62. The structures of these acetylated derivatives were based on 'H-NMR data. The presence of two tigloyl groups at C-1 1 and C-12 in anopterine was established on the basis of oxidation products of anopterine and anopteryl alcohol. Oxidation of anopterine with chromic acid in pyridine gave a diketone ditiglate, which on alkaline hydrolysis afforded the diketone 63. On the basis of the 'H-NMR spectra of the diketone 63 and its diacetate derivative 64,the authors established that the carbonyl group was not present at either C-1 1 or C-12 in 63. These results indicated that two tigloyl groups were present at C-1 1 and C-12 in anopterine.

2.

THE CHEMISTRY OF C,-,-DITERPENOID

OAc

ALKALOIDS

OR

&CHz

" ... .......,

0

R'O..

119

H,C------N

OH

CH, 0 54 60 61 62

R' = R 2 = AC R' = Ac, R 2 = H R' = H, RZ = AC R' = R 2 = H

63 R = H 64 R = A c

OH

65

Oxidation of anopterine with Jones reagent followed by alkaline hydrolysis afforded a monoketone, which was assigned probable structure 65. Reduction of the monoketone with sodium borohydride in methanol at room temperature gave a 4:1 mixture of two products, with anopteryl alcohol as the major product. Oxidation of anopteryl alcohol with Jones reagent yielded a yellow triketone and a diketone. The latter was not identical with the diketone 63. Structure 66 was assigned to the yellow triketone. Partial structure 67 was assigned to the diketone that was obtained from Jones oxidation of anopteryl alcohol. Further oxidation of 63 with chromic acid by the Jones method gave the yellow tetraketone 68.

67

68

120


On treatment with acetic anhydride in pyridine, the yellow tetraketone (68), the yellow triketone (66), and the diketone (67) afforded monoacetyl, diacetyl, and triacetyl derivatives, respectively. All these derivatives contained a tertiary acetoxyl group. However, comparisons of 'H-NMR spectra of the parent ketones with those of the acetyl derivatives indicated that a rearrangement of the molecule or a major conformational change must have occurred. On the basis of extensive 'H-NMR spectral analysis, structure 69 was proposed for the diacetyl derivative which was derived from the triketone 66. Structure 69 was justified on the basis of conformational arguments. 0

CH, OAc 69

Formation of the diacetyl compound (69) from the triketone (66) indicated that all of the ketones which underwent this anomalous acetylation reaction must have a C-2 0x0 group. Evidently a C-6 hydroxyl group is not necessary for this unusual acetylation reaction to form compounds such as 69. This idea was supported by the formation of only a monoacetyl derivative from the tetraketone (68). The conformational argument was that if ring A assumed a boat form, formation of an acetal at C-2 with an oxygen bridge between C-2 and C-5 could occur by reaction of the C-5 hydroxyl group with the C-2 0x0 group. Then ring B could assume a boat conformation with the piperidine ring changing from boat to chair form to minimize ring strain. On the basis of the arguments presented above, the tertiary acetoxyl group was assigned to C-2 in 69. Mild hydrolysis of 69 in dilute methanolic potassium hydroxide regenerated the original ketone 66, a result that indicated that no skeletal rearrangement was involved during this anomalous acetylation reaction. All the reaction products reported here were supported by detailed 'H-, 13C-NMR,and mass spectral data. In 1976, Lamberton and his colleagues reported (70)the isolation of two minor alkaloids, anopterimine and anopterimine N-oxide, from the leaves of A . macleuyanus F. Muell. These alkaloids were not encountered in the related species, A . glandulosus Labill. On the basis of extensive 'H- and 13 C-NMR analyses, structures 70 and 71 were assigned to anopterimine and anopterimine N-oxide, respectively.

2.


70 Anopterimine

121

71 Anopterimine N-oxide

During the isolation of anopterine, the Australian chemists isolated a new alkaloid, hydroxyanopterine, from the bark and leaves of A . macleayanus and A . glandulosus. A closely related new alkaloid, dihydroxyanopterine, was also encountered as a minor component in the bark of A. macleayanus. Comparison of the ‘H- and 3C-NMR spectral data of hydroxyanopterine and dihydroxyanopterine with those of anopterine afforded evidence for the partial structures 72 and 73 for hydroxyanopterine and dihydroxyanopterine, respectively. Each of these alkaloids has a hydroxyl group at C-1 or C-3 on the A ring. On the basis of the 13C-NMR assignments. the presence of the additional skeletal hydroxyl substituent was preferred at the C- 1 position. The presence of another hydroxyl group in an acid moiety of dihydroxyanopterine was confirmed by hydrolysis. Alkaline hydrolysis of hydroxyanopterine and dihydroxyanopterine gave the identical amino alcohol, a result which confirmed that the second hydroxyl group in dihydroxyanopterine was a part of a new hydroxytiglic acid moiety. A biosynthetic pathway for the Anopterus alkaloids has been proposed involving a hetisine-type precursor.

’

CH, OH 72 Hydroxyanopterine

73 Dihydroxyanopterine

122


111. Atishe-Type Alkaloids

A. ATISINE AND ISOATISINE Atisine, the principal alkaloid of the rhizomes of A . heterophyllum Wall, has been the subject of extensive study since 1942 because of its interesting chemical features and complex structure (72). In 1954, Wiesner and coworkers (72)proposed a gross structure for atisine and subsequently Pelletier and Jacobs (73) supported this structure independently. Later, the structure of atisine as 74 was confirmed by two total syntheses (74, 75). Recently, atisine has been isolated from A . heterophylloides (76),A . gigas Ler. et Van. (77)and A . antharu (16).Atisine is an amorphous strong base (pK, 12.5) that undergoes a facile isomerization of the oxazolidine ring to isoatisine (75) (pK, 10.3) by treatment with alkali or even by simple refluxing in methanol. Atisine and isoatisine form the corresponding quaternary immonium salts 5 and 76, respectively, by treatment with hydrochloric acid. Atisine and isoatisine can be regenerated from the corresponding immonium salts by treatment with base. Atisinium chloride (5) is more stable in refluxing polar solvents than isoatisinium chloride (76). One can quantitatively isomerize isoatisinium chloride to atisinium chloride by refluxing in DMSO, DMF, or high-boiling alcohols. Thus, depending on reaction conditions, atisine, and isoatisine can be interconverted easily. The stereochemistry of the oxazolidine ring of atisine has been of great interest for a long time. In 1968, Pelletier and Oeltmann (78) postulated on

5 Atisinium Chloride

76 Isoatisinium Chloride

2.

123


the basis of a 'H-NMR study that atisine exists as two different conformers of the piperidine ring (chair 77a and boat 77b) in 1 : 2 ratio, respectively, in CDC1, solution at room temperature. Subsequently, on the basis of a deuterium study, Pradhan and Girijavallabhan (79) suggested that atisine in solution is a mixture of isomers which differ in configuration at C-20 and which are interconvertible via a zwitterion. On the basis of a 13C-NMR study of atisine and related alkaloids, Pelletier and Mody (27, 28) demonstrated that atisine exists as a mixture of C-20 epimers 4a and 4b in nonionic solvents (e.g., chloroform, benzene etc.). The presence of two different sets of signals for the oxazolidine and piperidine rings in the I3C-NMRspectrum of atisine in CDCI, solution at room temperature suggested the existence of a pair of epimers. The fact that the oxazolidine ring of atisine is regenerated from atisinium chloride (5), in which (2-20 is trigonal, by treatment with base suggested that formation of the oxazolidine ring takes place from both sides of the trigonal C-20 carbon to give epimers 4a and 4b. Thus, atisine can be represented by structure 4, indicating the presence of both C-20 epimers in the same formula.

77b

77a

4 Atisine

y '

CH,

'

4a

CH,

CH, 4b

The structure of atisinium chloride as 5 was confirmed recently by a single-crystal X-ray analysis (30). The absolute configuration of atisinium chloride was determined as 4S, 5S, 8R, 10R, 12R, and 1 5 s by Hamilton's method and confirmed by examination of sensitive Friedel pairs. A recent X-ray crystallographic study of isoatisine confirmed the assigned structure 75. The absolute configuration was established as 4S, 5S, 8R,10R, 12R, 15S, and 19s for isoatisine. It is worth noting that isoatisine does not exist as a mixture of C - 19 epimers. Early work on the chemistry of atisine and isoatisine

124


has been described in detail in several reviews (6, 8, 13) published between 1960 and 1970.

B. DIHYDROATISINE AND ATIDINE Dihydroatisine, a minor alkaloid of the roots of A . heterophyllum Wall, was isolated (80) from the strong base fraction and its structure (78) was established by comparison with the sodium borohydride reduction product of atisine or isoatisine. Recently, an X-ray analysis of dihydroatisine confirmed (30)its structure and determined the absolute configuration as 4S, 5S, 8R, 10R, 12R, and 15s. So far dihydroatisine has not been reported in any other plant.

78 Dihydroatisine

79 Atidine

The isolation and structure elucidation of atidine (79), a minor alkaloid of the roots of A . heterophyllum Wall, was reported in 1965 (81).Atidine was chemically correlated with dihydroatisine (78) and dihydroajaconine, a reduction product of ajaconine (80).Reduction of atidine with sodium borohydride in 80% methanol afforded dihydroatidine, which was identical to dihydroajaconine. Huang-Minlon reduction of atidine furnished dihydroatisine. A I3C-NMR analysis of various C,,-diterpenoid alkaloids established (28) that the carbonyl group in atidine is present at C-7. Recentiy, the structure of atidine as 79 was confirmed by a single-crystal X-ray analysis (82). It is worth noting that there are intermolecular hydrogen bonds between the hydrogen of the C-22 OH group and oxygen of the C-7 group and between the hydrogen of C-15 OH and oxygen of C-22 in crystalline atidine. AND DIHYDROAJACONINE C. AJACONINE

Ajaconine, the major alkaloid of the seeds of Delphinium ajacis syn. Consolida ambigua (garden larkspur) and D. consolida, has been known since 1913 (83).Recently, ajaconine has been isolated from the whole plants of D . virescens Nutt (84)and D. carolinianum (85),two relatively rare plants native to the southeastern United States. In 1961, Dvornik and Edwards (86) reported a full account of the structure elucidation of ajaconine as 80.

2.


125

The chemical work on ajaconine has been reviewed ( 6 )in Volume XI1 of this treatise. Recently, Pelletier and Mody reported (87) an unusual rearrangement of ajaconine to 7%-hydroxyisoatisine(82) via a disfavored 5-endotrigonal ring closure, which is discussed in Section V.

81 Dihydroajaconine

80 Ajaconine

In 1978, dihydroajaconine was isolated (88) from the mother liquors accumulated during the isolation of ajaconine from garden larkspur (C. ambigua). On the basis of I3C- and 'H-NMR analysis, structure 81 was assigned to dihydroajaconine. Reduction of ajaconine with sodium borohydride in aqueous methanol gave a product that was identical with natural dihydroajaconine. 3C-NMR spectra of ajaconine, dihydroajaconine, and related alkaloids were also reported. It was suggested that dihydroajaconine may be an intermediate between ajaconine and atidine in the plant. In 1972, Sastry and Waller (89)reported the presence of dihydroajaconine during GC-MS studies of ajaconine isolated from D. ajucis. A sample of what had been earlier identified as pure ajaconine furnished a mixture of five compounds when the deuterated trimethylsilyl derivative was analyzed on the GC-MS. The temperature on the GC column (215") and the time required for elution (12.7-27.8 min) may have given rise to rearrangement products.

D. KOBUSINE AND PSEUDOKOBUSINE Kobusine has been isolated (52, 90-92) from A . sachalinense, A . yesoense Nakai, A . lucidusculunq and A . kamtschaticum, Aconitum species native to Japan. Okamoto and co-workers (93) initially assigned structure 83 or 84

126


to kobusine on the basis of extensive chemical and spectral studies. Later, the same group revised (94)the structure of kobusine to 85 without presentation of evidence to eliminate structure 84. After unsuccessful attempts to correlate hetisine with kobusine, in 1970 Pelletier and co-workers (95) reported the structure of kobusine as 86 on the basis of a single-crystal X-ray analysis of its methiodide. R2

?. .,

~..-

"'

N--- ..

OH

''

CH 3 83 R' 84

R'

CH 3

= OH,

R2 = H

85

= H. R2 = OH

2 : $

N - - - .~

OH

CH, R 86 R = H Kohusine 87 R = OH Pseudokobusine

By virtue of the previous correlation (93)of kobusine with pseudokobusine, structure 87 was assigned to pseudokobusine. The latter was also isolated along with kobusine from A . yesoense Nakai and A . lucidusculum Nakai (91). The chemistry of kobusine and pseudokobusine has been discussed ( 6 )in a previous chapter in this treatise. Japanese chemists (96)have reported the chemical conversion of kobusine into the chloramine (95). The latter was treated with sodium methoxide in methanol to afford compound 96 in which the bridged C-14-C-20 bond was cleaved. Reduction of kobusine with sodium in n-propanol, followed by acetylation afforded compound 88. Treatment of 88 with excess phenyl chloroformate in refluxing o-dichlorobenzene gave the carbamate 89. The latter was hydrogenated over Pd-C in methanol to obtain compound 90 in 94% yield. Further hydrogenation of 90 in the presence of platinum in acidic solution gave 91. Acidic hydrolysis of 91 afforded compound 92. The carbamate 92 was converted to the benzyl derivative 93 by treating with

2.

127


benzyl alcohol and sodium hydride in dimethoxyethane. Hydrogenation of 93 over Pd-C in acidic methanol yielded 94 in 95% yield. The latter was chlorinated with N-chlorosuccinimide to afford the chloramine 95 in good yield.

86

88

90

89

I 91 R’ = Ac, R 2 = C6H5

92 R’ 93 R’

= H,

RZ = C,H5 = H, RZ = CHzC6H5

94 R = H 95 R = CI

Treatment of the chloramine 95 with sodium methoxide in refluxing methanol afforded a mixture of products 96,97, and 98 in 36%, 28%, and 13% yield, respectively. The structure and stereochemistry of 96 was established by X-ray analysis. Reduction of 96 with sodium borohydride in methanol afforded 99. The latter was acetylated with acetic anhydride in pyridine and subsequently hydrolyzed with hydrochloric acid to give the

128


V.

MODY

N-acetate 100. Dechlorination of 100 was effected by Raney nickel hydrogenolysis to afford compound 101 in 50% yield. The cleavage of the C-14C-20 bond in the chloramine 95 is a novel fragmention for which no satisfactory mechanism has been offered.

96

91

,.CH,

99 R'

= C1,

R2 = H

98

100 R' = C1, R2 = AC 101 R' = H, R 2 = AC

E. IGNAVINE AND ANHYDROIGNAVINOL Ignavine was isolated by Okamoto and co-workers (97) in 1952 from the roots of A . sayoense Nakai. Subsequently, this alkaloid was also isolated from the roots of A . tasiromontanum Nakai (97, 98) and A . japonicum (99). Alkaline hydrolysis of ignavine gave an amino alcohol, anhydroignavinol, and benzoic acid. On the basis of spectral and chemical studies (loo),the tentative structures 102 and 103 were assigned to ignavine and anhydroignavinol, respectively. Anhydroignavinol was reported to have a molecular formula of C20H25N04 (MW 343) and was assumed to arise from hydrolysis of the benzoate ester

102

103

2.


129

at C-3 and the formation of an ether group by dehydration of two hydroxyl groups of ignavine. A high-resolution mass spectral study by Pelletier's group (101) indicated that the molecular ion of anhydroignavinol was m/e 345.1936 and therefore the molecular formula must be C,oH27N0,. In 1970, Pelletier, Page, and Newton (101) reported the correct structure 104 for anhydroignavinol from a single-crystal X-ray analysis of its methiodide.

104 Anhydroignavinol

Since previous work led to assignment of the benzoate group at C-3 in ignavine, the position and functionality of the remaining oxygen required by the ignavine formula, C2,H3,N06, requires explanation. Either the molecular formula originally assigned to ignavine is incorrect and should be C2,H3,N0, or an unusual rearrangement occurs during the hydrolysis of ignavine to anhydroignavinol. Considering the correct structure for anhydroignavinol, ignavine may be a hydrate of the benzoate ester of anhydroignavinol. The position of the benzoate group in ignavine still needs to be determined. Earlier work on ignavine and anhydroignavinol has been reviewed in Volume XI1 of this treatise (6).

F. HYPOCNAVINE AND HYPOGNAVINOL Hypognavine was first isolated from certain varieties of A . sanyoense Nakai in 1953 by Okamoto and co-workers (102). Alkaline hydrolysis of hypognavine afforded an alkamine, hypognavinol. On the basis of extensive chemical studies and spectral data, the Japanese chemists (102-104) assigned either structure 105a or 105b for hypognavine and structure 106a or 106b for hypognavinol. Since PMR spectral examination of hypognavinol was unsuccessful in differentiating structures 106a and 106b, the structure of hypognavinol was established as 107 (105) from a single-crystal X-ray analysis of its methiodide. On the basis of steric effects, Sakai (104) proposed that the benzoate group of hypognavine is in a /?-configuration. A careful examination of models suggested that the steric difference between a C-1 P-benzoate group and a C-2 a-benzoate group would be slight. Therefore, the location of the benzoyl group in hypognavine remains uncertain.

130


105a R = Bz 106a R = H

105b R = Bz 106b R = H

OH 1

CH, 107 Hypognavinol

G. ISOHYPOGNAVINE

Isohypognavine has been isolated (99, 106) from the roots of A . majijai Nakai and A . juponicurn Thumb. Its name is unfortunate since it is not an isomer of hypognavine. This alkaloid has not been isolated from any other Aconitum species. On alkaline hydrolysis, isohypognavine gave an alkamine known as isohypognavinol. On the basis of chemical correlation (107) of isohypognavine with kobusine, the partial structures 108 and 109 were HO.

,CH,

108

109

110 R = Bz Isohypognavine 111 R = H Isohypognavinol

2.


131

assigned to isohypognavine and isohypognavinol, respectively. Although isohypognavine has been known more than 30 years, the complete structure has not been established. Early chemical work on these two compounds is discussed in Volume XI1 of this treatise (6). On the basis of the stereochemistry of the C-11 and C-15 hydroxyl groups in related alkaloids (e.g., kobusine, pseudokobusine), the C-1 1 and C-15 hydroxyl groups are most likely in a p-configuration in isohypognavine and isohypognavinol. We can therefore tentatively suggest structures 110 and 111 for isohypognavine and isohypognavinol, respectively.

H. DENUDATINE In 1961, Singh (108) isolated denudatine (C,,H,,NO,, MW 331) as a minor alkaloid of the roots provisionally identified as D.denudutum Wall. On the basis of chemical and spectral evidence, Indian chemists (109, 110) tentatively assigned structure 112 to denudatine. Later work indicated that the 'H NMR and mass spectra of denudatine did not agree with the assigned structure. Canadian (111) and American (112) chemists independently showed that the correct molecular formula for denudatine is CZ2H3,NO2as evidenced by the mass spectrum (mle 343). The 'H-NMR spectrum of denudatine revealed the absence of an N-methyl group. On the basis of spectral and degradation studies, Wiesner and Gotz (111) indicated that denudatine can be assigned any one of four possible structures 113,114,115, or 116, in which C-20 could be connected to C-7 or C-14 and the secondary hydroxyl group can be at C-1 1 or C-13. Subsequently, Brisse (113) and the American investigators (112) reported independently a single-crystal X-ray diffraction analysis of denudatine and its methiodide and established the structure and stereochemistry of denudatine as 117. It is noteworthy that denudatine is the first C,,-diterpenoid alkaloid with an atisine skeleton possessing both an N-ethyl and a C-7-C-20 bridge. The biosynthetic implications of this alkaloid were mentioned by the Canadian chemists (212). RZ

OH

112

113 114

R' = OH, RZ = H R' = H. RZ = OH

132


115 R’ = OH, R2 = H 116 R’ = H . R 2 = OH

117 Denudatine

I. VAKOGNAVINE Vakognavine has been isolated by Singh and Singh (114)from the indigenous crude drug known as “uakhma”, which was identified as the roots of A . palmatum Don. On the basis of the isolation of 1,9-dimethyl-7-ethylphenanthrene from the selenium dehydrogenation products, Singh and Jaswal (115) postulated a songorine-type skeleton (118) for vakognavine. Spectral data revealed the presence of a tertiary methyl, an N-methyl, a benzoate, and three acetate groups in vakognavine. They also mentioned (115)that vakognavine is an highly oxygenated alkaloid of the atisine group. In 1971, Pelletier and co-workers (116) reported a single-crystal X-ray analysis of vakognavine hydriodide (119) and established the structure of vakognavine to be 120. The presence of the C-19 aldehyde in vakognavine was indicated by a singlet at 6 9.43 in the ‘H-NMR spectrum in chloroform solution. The aldehyde singlet disappeared on the addition of trifluoroacetic acid and the unchanged free base was recovered on basification. Later Singh and co-workers (117) published additional chemical and spectral data supporting structure 120 for vakognavine. On hydrogenation with Adams catalyst, vakognavine gave the hexahydro compound 121 in which the exocyclic double bond and both the carbonyl groups were reduced. Vakognavine formed a bishydrazone, which was characterized as the

118

119

2.

THE CHEMISTRY OF Cz,-DITERPENOID ALKALOIDS

133

BzO..

120 Vakognavine

OH

'5.

OH 121

0

\\

122 R' = Bz, R Z = Ac 123 R' = H, R 2 = Ac 124 R' = R 2 = H

reineckate salt. Selective hydrolysis of vakognavine with 50% sulfuric acid yielded compound 122 after 4.5 min, the monoacetate 123 after 13.5 min and the completely hydrolyzed product 124 after 2 hr. The structures of the hydrolysis products were based on 'H-NMR data. Vakognavine is the first example of an N, C- 19-seco-diterpenoid alkaloid reported and an interesting alkaloid for biogenetic speculation. The authors (116) suggested that the C-19 aldehyde may be a plausible alternate to the pseudokobusine structure as an intermediate in the biosynthesis of the modified atisine-type skeletons such as hetisine. The C-19 hydroxyl of vakognavine hydriodide (119) is reminiscent of the oxazolidine oxygen of isoatisine. J. HETISINE (DELATINE) AND HETISINONE Hetisine (125) was isolated as a minor alkaloid from the roots of A . heterophyllurn Wall (80)in 1942 by Jacobs and Craig (118, 119). Later it was also isolated from D.cardinale Hook (120).Several papers were published (121, 122) regarding the chemistry and structure elucidation of hetisine, but the structure of hetisine (125) was eventually established by an X-ray diffraction study (123. 124). Earlier work on the chemistry of hetisine has been reviewed in Volume XI1 of this treatise (6).

134


RO

om RO\

R 0 . . H H 2

N---

HO H O . . e Z

__

:, CH3 125 R 126 R

H Hetisine = AC =

127 R 128 R

=

AC Hetisinone

=H

RO

130 R = H 131 R = MS

133

During an attempted chemical correlation of hetisine and kobusine, Wright, Newton, and Pelletier (125) observed an unusual rearrangement of a hetisine derivative to a cyclopropane derivative by lithium aluminium hydride reduction. The correlation route involved oxidation of hetisine diacetate (126) to the ketodiacetate 127, and hydrolysis to hetisinone (128). Wolff-Kishner reduction of hetisinone gave the diol 129. Selective Sarett oxidation of 129 yielded compound 130, which was converted into the mesylate 131. Theoretically, reduction of the latter and introduction of an allylic hydroxy group should have produced kobusine (86).However, lithium aluminium hydride reduction of 131 afforded the cyclopropane derivative 132. The 'H-NMR spectrum of 132 indicated the presence of an extra tertiary methyl group at 6 1.18, which was considerably more deshielded than any of the tertiary methyl groups previously encountered in this type of alkaloid. The structure of 132 was established (125) by an X-ray analysis of its methiodide. The authors suggested that coordination of the oxygen of the mesylate group with some aluminium species provided at least partial ionization, and then hydride attack on species 133 could have occurred at C-17 to give the cyclopropyl compound 132. This reaction represented the first reported example of this type of skeletal rearrangement among the C,,-diterpenoid alkaloids.

2.


135

Hetisinone (128) has been reported to occur in D . cardinale (120), D . denudatum (126),and A . heterophyllum (80).Structure 128 originally assigned for hetisinone was confirmed (127) by ‘H-NMR and mass spectral studies. Two other possible structures for hetisinone (134 and 135) were discarded on the basis of the following arguments.

134

135

Dehydration of hetisine diacetate (126) with phosphorus oxychloride and pyridine followed by basic hydrolysis afforded a mixture of olefins 136 and 137, whose structures were analyzed by ‘H-NMR spectroscopy. These olefins can only be derived from hetisine diacetate if its structure is 126, a fact requiring the structure of hetisinone to be 128. Furthermore, hetisinone is stable to bases, behavior that is consistent with the assigned structure but less likely for either of the alternative B-ketoalcohols 134 and 135. When hetisinone was heated in D,O-CH,OD containing sodium deuteroxide, a mixture of deuterated hetisinones was obtained. Mass spectral analysis revealed the presence of 14% d , , 53% d,, 24% d , , and 6% d4 species. These data further confirmed that hetisinone is correctly represented as 128.

K. HETIDINE Hetidine has been isolated (80) in very small quantity from the strongly basic fraction of the extracts of the roots of A . heterophyllwn Wall. The presence of an N-methyl group, a tertiary methyl group, two acetylable hydroxyl functions, two ketones, and an exocyclic double bond in hetidine

136


was revealed by chemical and spectral data. Because hetidine was not available in sufficient quantity, the structure of this alkaloid was established by a single-crystal X-ray analysis of hetidine hydriodide (128). The latter was prepared by prolonged treatment of hetidine with methyl iodide in dimethylformamide. The structure of hetidine hydriodide was established as 138; thus hetidine was assigned structure 139. The masked aminoketone group of hetidine hydroiodide is analogous to that existing in pseudokobusine and miyaconitine.

HO..

138

139 Hetidine

L. MIYACONITINE AND MIYACONITINONE Miyaconitine and miyaconitinone, two highly oxygenated alkaloids, were isolated from the Japanese species A . miyabei Nakai in 1946 (129).On the basis of chemical and spectral data (54, 129-132) and biogenetic considerations, structures 140 and 141 were assigned to miyaconitine and miyaconitinone, respectively. High-resolution mass spectra confirmed the earlier established molecular formula, C,,H,,NO, , for miyaconitine and C,,H,,NO, for miyaconitinone. Both alkaloids failed to form acetylation products with either acetyl chloride or acetic anhydride in pyridine. These alkaloids have been correlated by converting miyaconitine to miyaconitinone by oxidation with CrO, or Bi,O, in acetic acid. Hydrogenation of miyaconitine over platinum in ethanol gave its dihydro derivative. Acidic hydrolysis of miyaconitinone afforded miyaconinone (143). The latter was reconverted to 141 by acetylation with acetyl chloride. Oxidation of 143 with CrO, in sulfuric acid or MnO, in chloroform yields the dehydro derivative 144. On formation of the perchlorates of miyaconitine and miyaconitinone, the remarkably low frequency (1678and 1676 cm-') IR carbonyl maxima disappeared. In addition, the absorption at 2 ,,,432 nm (log E l.6),which is characteristic of an x-diketone moiety, also disappeared in the W spectrum of miyaconitinone perchlorate. Miyaconitine has been shown to contain an a-ketol group, whereas miyaconitinone contains an x-diketone moiety. On the basis of spectral analysis of compound 144, the authors suggested that the new

2.


137

carbonyl formed in compound 144 by oxidation of 143 has an adjacent active methylene group and is near the nitrogen atom. On the basis of spectral data and the color tests, the Japanese chemists (132)represented structures 140 and 141 for miyaconitine and miyaconitinone, respectively. Subsequently, the structure of miyaconitine was confirmed by a single-crystal X-ray analysis of its hydrobromide (142) (133). 0

\\

140 Miydconitine

141 R = Ac Miyaconitinone 143 R = H

144

0 &H2 HRO..@ C . . ...N 5

'OR

:, H CH,

0

145 R = H Miyaconine

146 R

=

Ac

147 R = H Apomiyaconine 148 R = Ac

In 1974, the same workers (134)reported an unusual skeletal rearrangement of miyaconitine. Treatment of miyaconitine (140)with 1 N methanolic potassium hydroxide for 1 hr yielded miyaconine (145). The latter on acetylation with acetyl chloride afforded diacetylmiyaconine (146). Reaction of miyaconine with 1 N methanolic potassium hydroxide under reflux for 2 hr yielded apomiyaconine (147).Acetylation of the latter with acetic anhydride in the presence of a catalytic amount of p-toluensulfonic acid on a steam

138


bath for 1 hr afforded diacetylapomiyaconine (148).Treatment of compound 143 with 5% hydrochloric acid under reflux for 2 hr also afforded miyaconine (145). The latter was also obtained by mild oxidation of miyaconitine (140) with an alkaline solution of triphenyltetrazolium chloride (TTC) at room temperature. The structures of miyaconine (145) and apomiyaconine (147) were assigned on the basis of 'H- and 13C-NMRdata. Complete assignments of 3C chemical shifts of 145 and 147 are also presented by the authors. On the basis of I3C-NMR data and Dreiding models, the Japanese workers assigned a P-configuration to the hydrogen at C-5 in 145 and 147. Miyaconitine and miyaconitinone were postulated as biogenetic intermediates in the formation of the modified atisine-type compounds from the normal atisine-type system.

'

M. DELNUDINE During the isolation of denudatine, Gotz and Wiesner (135)also isolated a new alkaloid, designated as delnudine (149),from the seeds of D.denudutum. Preliminary spectral data revealed the presence of two hydroxyls, a cyclohexanone, and an exocyclic double bond in proximity with the ketone. The presence of the tertiary carbinolamine moiety was demonstrated by the formation of a basic diacetate (150) and a neutral 0,N-diacetate (151) on acetylation with acetic anhydride in pyridine. They demonstrated that one of the ketones in compound 151 was derived from the carbinolamine moiety. Finally, the structure of delnudine was established as 149 by a single-crystal

HO..

149 Delnudine

151

150

125 Hetisine

2.


139

X-ray analysis (136) of delnudine hydrochloride. It is worth noting that delnudine represents a novel type of skeleton. The Canadian chemists (135) speculated that delnudine may be biogenetically derived from hetisine (125) by the concerted rearrangement portrayed by the arrows in structure 125 and by introduction of the carbinolamine moiety.

N. SPIRADINE A, SPIRADINE B, AND SPIRADINE C In 1964 Molodozhnikov and co-workers (137) reported the isolation of several diterpenoid alkaloids from the shrub Spiraea japonica L. fil. of the Roseaceae family. Later Goto and co-workers (138) examined alkaloids of the same plant (Japanese name “Shimotsuke”) and isolated 10 new alkaloids. The structures of 3 of these, spiradine A (152), spiradine B (153), and spiradine C (154) have been determined by chemical correlations coupled with a single-crystal X-ray analysis (139) of spiradine A methiodide (155). Reduction of spiradine A with sodium borohydride in methanol at room temperature afforded spiradine B. Oxidation of the latter with CrO, in pyridine regenerated spiradine A. Hydrolysis of spiradine C with potassium hydroxide in ethanol yielded spiradine B. Treatment of spiradine A with acetic anhydride in pyridine gave an 0-acetate (156) and an N-acetate (157). The structures of these acetylation products were based on IR and ‘H-NMR data. When treated with methyl iodide in methanol, spiradine A gave a

152 R = H Spiradine A 156 R = AC

153 R = H Spiradine B 154 R = Ac Spiradine C

0

CH, 0 155

157

140


V.

MODY

methiodide (155), which was treated with silver oxide in 50% aqueous methanol to yield an N-methyl diketone (158). The latter was heated with methyl iodide at 100" in a sealed tube followed by treatment with silver oxide to afford 159. These transformations provided evidence for the I -N-C-CH,-& functionality in spiradine A. Finally, the structure OH

of spiradine A was determined by an X-ray analysis (138, 139). With the structure of spiradine A elucidated as 152, the structures of spiradine B (153), and spiradine C (154) were assigned accordingly.

0. SPIRADINE D AND SPIREDINE Spiradine D was also isolated from S. japonica by Goto and Hirata (140) in 1968. The structure of spiradine D (160) was elucidated by chemical correlation between spiradines A and D.

160 Spiradine D

161

2.


141

Spiradine D formed a quaternary salt (161)on treatment with methanolic hydrochloric acid at 0'. This salt was reconverted to spiradine D by shaking with silver oxide in methanol. This experiment suggested that spiradine D has a masked aminoketone group as exists in other diterpenoid alkaloids (e.g., hetidine). The presence of a carbinolamine ether (N-C-0-C) linkage in spiradine D was detected by the following chemical transformations. Reduction of spiradine D with sodium borohydride in methanol afforded compound 162. The latter was hydrogenated in ethanol to give the dihydro derivative 163. Spiradine D was correlated with spiradine A through this dihydro derivative. Spiradine A was converted to the azine 164 by treatment with hydrazine in diethylene glycol at 180" and then with

164

166

165

167

acetone at 20'. Wolff-Kishner reduction of 164 gave a mixture of compounds 165 and 166. When this mixture was heated at reflux with ethylene chlorohydrin and methanol in the presence of potassium carbonate, the N-P-hydroxyethyl derivative 167 was obtained. Catalytic hydrogenation of 167 in ethanol gave the dihydro derivative 163. The latter was identical to one prepared from spiradine D. On the basis of this chemical correlation, structure 160 was assigned for spiradine D. Spiredine has been isolated recently from S. juponicu by Gorbunov and co-workers (141). On the basis of spectral data and chemical correlation with spiradine A, structure 168 was assigned to this new alkaloid. Catalytic hydrogenation of spiredine in a mixture of ethanol and acetic acid afforded tetrahydrospiredine (169). The latter was identical with the compound obtained by the addition of ethylene oxide to dihydrospiradine A (170).

142


P. SPIRADINE F AND SPIRADINE G In 1968, Toda and Hirata (142) reported the isolation and structure determination of two major alkaloids of S. juponicu, spiradine F and spiradine G. Spiradine F is an acetate of spiradine G. On the basis of extensive chemical and spectral studies, the Japanese chemists (142) assigned structures 171 and 172 to spiradine F and spiradine G, respectively.

171 R = Ac Spiradine F 172 R = H Spiradine G

173

2.


143

The presence of a tertiary methyl group and an exocyclic double bond in spiradine G was demonstrated by 'H-NMR analysis. Mild reduction of spiradine G with sodium borohydride afforded the trio1 173, which indicated that the remaining two oxygen atoms exist as a part of two carbinolamine ether (N-C-0-C) linkages in spiradine G. The presence of an exocyclic double bond in the six-membered ring was confirmed by catalytic hydrogenation of spiradine G to compound 174 and oxidation of 172 with potassium permanganate to compound 175.

177

176

178

Oxidation of 172 with chromium trioxide in pyridine gave the monoketone 176, whereas oxidation of spiradine F under the same conditions afforded the hydroxylactam 177. Catalytic hydrogenation of compound 176 afforded the a-ketol 178. The latter was treated with sodium methoxide in benzene to give an enolated a-diketone (179), which definitely fixed the position of the hydroxyl group at C-6 in spiradine G. Comparison of an ORD curve of compound 178 with that of 5a-cholestane-6-one established the indicated absolute configuration for these alkaloids. It is worth noting that these alkaloids bear many structural similarities to the earlier mentioned alkaloid ajaconine. Q. SPIREINE

In 1964, Soviet chemists (137)reported the isolation of a new alkaloid, spireine, from S. japonica and later they proposed (143) alternative structures 180 or 181 for this new alkaloid. Chemical and spectral studies

144


revealed the presence of two keto groups, a tertiary hydroxyl group, two tertiary methyl groups, and an exocyclic double bond in spireine.

180

181

CHO

184

On reduction, spireine afforded di- and tetrahydro derivatives. The location of two keto groups in spireine was revealed by 'H-NMR and mass spectral analysis of deuterated spireine and tetrahydrospireine. When spireine was heated with selenium at 340", a compound with molecular formula C20H2,N0, was obtained. Structure 182 was proposed for this compound on the basis of spectral data. Since the C-19 imine bond is usually unstable and cannot be isolated in that form, we suggest that the imine bond is present at C-20 rather than at C-19 in the selenium degradation product (C,oH2,N0,). Thus, structure 183 should be considered for the latter. Each of the structures considered for spireine has unusual features. The exocyclic double bond in 181 bears some resemblance to lycoctamone (184), a rearrangement product of lycoctonine.

1V. Bisditerpenoid Alkaloids

A. STAPHISINE AND STAPHIDINE In 1941, Jacobs and Craig (144) reported the isolation of a diterpenoid alkaloid designated as staphisine from the seeds of D. straphisagria. On the basis of chemical studies (144, 145), they indicated that staphisine is (Iater a diterpenoid aIkaloid dimer with molecular formula C,,H,,N,O

2.


145

revised to C4,H60N,0) (146), which contains two NCH, groups and no methoxyl group (despite the presence of 1.36% OCH,). During the column chromatographic separation of staphisine they found that the combustion analysis of several samples of staphisine fluctuated between the limits of 82.13 and 82.85% for carbon and 9.47 and 9.77% for hydrogen. On the basis of this observation, Jacobs and Craig cautioned that the so-called staphisine could still be a persistent mixture of bases which are very difficult to separate. Attempts to separate “staphisine” by crystallization of the hydrobromide, hydrochloride, and nitrate salts met with failure.

H,C--

185 R = OCH, Staphisine 187 R = H Staphidine

H,C--

186

From the same mother liquors, in 1972 Pelletier and co-workers (247) isolated a methoxyl group-containing bisditerpenoid alkaloid, which they named staphisine, and elucidated its structure as 185 by X-ray analysis of its monomethiodide (186). Chemical studies of staphisine were hindered by its instability to light and heat and by the fact that attempted degradation led to complex changes involving numerous unstable products. Highresolution mass spectral and elemental analysis of staphisine established its molecular formula as C,,H,,N,O,. The presence of two tertiary methyl groups, two N-methyl groups, a cyclopropyl ring, a methoxyl group, and a conjugated double bond in staphisine was revealed by I3C-NMR, PMR, IR, and UV spectal data. Jacobs’ selenium dehydration experiments had afforded pimanthrene and 1,3-dirnethyl-7-isopropylphenanthreneas degradation products, which are compatible with structure 185. Thus, the structure of staphisine (185) elucidated by X-ray analysis is in agreement with observed spectral and chemical data for Jacobs’ staphisine.

146


In 1976, the same group (148) found that Jacobs' "staphisine" is a mixture of alkaloid 185 and a companion nonmethoxyl-bearing alkaloid designated as staphidine, C4,H,,NZ0. The structure of staphidine (187) was elucidated by a comparison of its 'H- and I3C-NMR, IR, UV, and mass spectra with those of staphisine (185). The presence of a conjugated diene system was confirmed by observing UV absorption at i,,, 268 nm ( E 17,300). The IR spectrum exhibited no N H or OH absorption. The mass spectrum showed an intense molecular ion peak at mje 606 corresponding to the molecular formula, C4,H5,N,0. The 'H-NMR spectrum of staphidine revealed the presence of two tertiary methyl groups at 6 2.13 and 6 2.21 and a vinyl proton at 6 5.85. Comparison of its 'H-NMR spectrum with staphisine showed the absence of a methoxyl singlet at 6 3.30 and an upfield shift of one N-methyl group from 6 2.27 to 6 2.21 in staphidine. The observed change (A6 = 0.06) in the chemical shift of the N-methyl was explained by the steric interaction between the NCH, and OCH, group in the A unit of staphisine. On the basis of this observation, the chemical shift at 6 2.13 was assigned to the N-methyl group in unit B of staphisine and staphidine and that at 3 2.27 and 2.21 to the N-methyl group in unit A in staphisine (185) and staphidine (187), respectively. Further correlation of staphidine with staphisine was made through their respective I3C-NMR spectra. This comparison afforded evidence for the absence of a methoxyl group at 57.8 ppm and a C-13 methine carbon at 89.4 ppm in staphidine. Based on these data, structure 187 was assigned to staphidine.

B. STAPHININE AND STAPHIMINE Besides the two bisditerpenoid alkaloids discussed earlier, two new iminecontaining alkaloids designated as staphinine and staphimine have been isolated (148)from the seeds of D.stuphisagria. The structures of staphinine (188) and staphimine (189) were also assigned on the basis of I3C- and 'H-NMR spectral analysis. The 'H-NMR spectrum of staphinine revealed the presence of two angular methyl groups at 6 0.94 and 6 1.00, one N-methyl group at 6 2.13, a methoxyl group at 6 3.30, a vinyl proton at 6 5.85, and an imine proton at 6 7.30. The 'H-NMR spectrum of staphimine was similar except for the absence of a methoxyl singlet at 6 3.30. The 'H-NMR data indicated that these two alkaloids are very similar to each other and are related to the earlier reported alkaloids staphisine and staphidine. The presence of an imine (-N=CH-) group in staphinine and staphimine was established by comparison with 3C-NMR shifts of known atisine derivatives containing an imine group, e.g., atisine azomethine. The presence of an imine group in the A unit of these alkaloids was consistent with the observed downfield

'

2.

THE CHEMISTRY OF C, 0-DITERPENOID ALKALOIDS

147

188 R = OCH, Staphinine 189 R = H Staphimine

shift of the C-4 carbon and the upfield shift of the C-20 carbon in staphinine (188) and staphimine (189) relative to the known alkaloids staphisine and staphidine, respectively. This was also confirmed on the basis of an N-methyl singlet at 6 2.13 in the 'H-NMR spectrum of both alkaloids. On the basis of these spectral data, structures 188 and 189 were assigned to staphinine and staphimine, respectively. The authors were unable to carry out any transformation of staphinine and staphimine to staphisine and staphidine, respectively, because of the instability of these alkaloids toward various mild reducing agents (e.g., sodium borohydride, sodium cyanoborohydride). Staphimine and staphinine occur in extremely small amounts in the seeds of D . stuphisagria. It has been suggested that the imine-containing alkaloids may be biogenetic precursors of staphisine and staphidine.

C. STAPHIGINE AND STAPHIRINE Staphigine and staphirine have been isolated (149) in extremely small amounts from the seeds of D. stuphisagria. Staphigine and staphirine are the C- 19 lactam derivatives of staphisine and staphidine, respectively. The structures of staphigine (190) and staphirine (191) were determined on the basis of their I3C- and 'H-NMR spectra. The IR spectra of these alkaloids revealed the presence of a lactam. The H-NMR spectrum of staphigine indicated the presence of two tertiary

'

148

S. WILLIAM PELLETIER AND NAFESH V. MODY

Y H,C--

190 R 191 R

= OCH, =H

Staphigine Staphirine

methyl groups at 6 0.94 and 1.12, two N-methyl groups at 6 2.13 and 2.98, a methoxy singlet at 6 3.30, and a vinyl proton at 6 5.85. The 'H-NMR spectrum of staphirine was identical to that of staphigine except for the absence of a methyl singlet at 6 3.30. The downfield tertiary methyl singlet at 6 1.12 in these alkaloids confirmed the presence of the lactam and this value was in perfect agreement with the value observed for the methyl singlet (6 1.12) of the atisine lactam derivative (192). The presence of the lactam in the A unit of these alkaloids was established by the appearance of an N-methyl singlet at 6 2.13 in the 'H-NMR spectra and the constant 13Cchemical shifts shown by the C-19, C-20, and NCH, carbons of staphigine and staphirine by comparison with the known alkaloids staphisine (185), staphinine (188), and staphimine (189). The authors indicated that these lactam alkaloids did not arise as artifacts by oxidation of staphisine and staphidine during isolation.

D. STAPHISAGNINE AND STAPHISAGRINE Staphisagnine (193) and staphisagrine (194) were also isolated (1.50) in extremely small amounts from the mother liquors accumulated during the isolation of delphinine from the seeds of D. stuphisagria. These alkaloids are unusual in containing an oxazolidine ring of the atisine and veatchine type in addition to many of the uncommon features of the staphisine skeleton.

2.


149

H,C--

193 R = OCH, Staphisagnine 194 R = H Staphisagrine

The IR and 'H- and I3C-NMR spectra of these alkaloids showed some similarity to the known alkaloids staphisine (185) and staphidine (187). The 'H-NMR spectrum of staphisagnine revealed the presence of two tertiary methyl groups at 6 0.82 and 0.93, one N-methyl group at 6 2.27, a proton as part of an oxazolidine methoxyl group at 6 3.30, an N-CH-0 ring at 6 4.06, and a vinyl proton at 6 5.93. The 'H-NMR spectrum of staphisagrine was identical to that of staphisagnine except for the absence of a methoxyl singlet at 6 3.30. The presence of the oxazolidine ring in the B unit of these alkaloids was established by 'H-NMR analysis. The latter was confirmed through a comparison of their 13C chemical shifts with those of the known oxazolidine ring-containing alkaloids, veatchine, garryine, atisine, and isoatisine. It is interesting to note that these two bisditerpenoid alkaloids did not contain the conjugated diene system, which is present in the other six bisditerpenoid alkaloids. Biogenetically, it is worth noting that all these bisditerpenoid alkaloids occur as methoxyl and desmethoxyl pairs in the seeds of D.staphisagria.

V. Behavior and Formation of the Carbinolamine Ether Linkage in Diterpenoid Alkaloids: The Baldwin Cyclization Rules Recently, Pelletier and Mody (87) reported an unusual rearrangement of ajaconine (80), via a disfavored 5-endo-trig ring closure, to the more stable oxazolidine ring-containing compound, 7cc-hydroxyisoatisine (82). They called attention to apparent violations of Baldwin's cyclization rules (151)

150

S. WILLIAM PELLETIER A N D NARESH

V.

MODY

MeOH

OH 80

82

in certain of the carbinolamine ether (N-C0-C) linkage-containing diterpenoid alkaloids and their derivatives (152). Results on 5- and 6-endotrig cyclizations involving nucleophilic attack of oxygen on immonium salts derived from C,,-diterpenoid alkaloids will be discussed in this section. Atisine, an amorphous alkaloid (pK, 12.5), is usually isolated in the form of its hydrochloride salt, a compound that is really a tertiary immonium salt (5). Atisine (4) can be regenerated from atisinium chloride by treatment with base. The fact that the oxazolidine ring closes in two different directions to give a pair of epimers suggested the operation of unusual constraints on the mechanism of ring closure. Examination of a Drieding model of atisinium chloride revealed that closure of the oxazolidine ring on the pro-20R side of the plane is sterically hindered, especially by H-14, which is situated almost directly over C-20. Across to the pro-20s side of the bond is almost equally restricted by H-2. The authors indicated that cyclization of the ternary immonium salt to form the five-membered oxazolidine ring is an example of a “disfavored” 5-endo-trig ring closure. Yet this ring closure is a very facile one. The same phenomenon was also observed during the conversion of isoatisinium chloride (76)to isoatisine (75), of veatchinium chloride (3) to veatchine (l),and of garryfoline hydrochloride to garryfoline. The formation and behavior of five- and six-membered carbinolamine ethers in various diterpenoid alkaloids were examined to determine whether any further violation of Baldwin cyclization rules occurs in these alkaloids. In 1957, Marion and co-workers (153) reported the preparation of several six-membered ring-containing carbinolamine ethers from C, ,-diterpenoid

4 Atisine

5 Atisinium chloride

2.


75 Isoatisine

151

76 Isoatisinium chloride

alkaloid derivatives. Subsequently, dehydrocondelphine (196) was prepared (152) from condelphine (195) by treatment with aqueous potassium permanganate. Dehydrocondelphine is a weak base that forms a ‘NH-type salt (197) with hydrochloric acid rather than the Schiff salt (198). This behavior is not because of a special stability of six-membered carbinolamine ethers, but due to the prohibitively high energy of the transition state for the opening of the ether (196) to the quaternary Schiff salt (198). Examination of the Drieding model for 198 indicated that this Schiff salt cannot close easily to the ether for steric and vectorial reasons. Consequently, the transition state for 0-protonation and opening of the ether linkage of dehydrocondelphine to the Schiff salt would be expected to be unfavorable.

OCH,

OCH,

196

195

OCH,

OCH, 197

198

The oxazolidine rings (199) of C,,-diterpenoid alkaloids in hydroxylic solvents such as methanol are in equilibrium with the corresponding Schiff salts (200) and consequently are strong bases. Examination of a Drieding model of such a Schiff salt indicated that it is vectorially poorly arranged for ring closure. Although such a cyclization is “disfavored” according to

152


Baldwin’s rules, experimental evidence demonstrated (154) that an equilibrium does exist between the oxazolidine ring (199) and the Schiff salt (200). This observation suggests that the Baldwin rules are less prohibitive for quaternary immonium salts bearing a full charge on the nitrogen. These salts resemble carbocations to a greater extent than uncharged groups. The authors indicated that an attack on a carbocation (201) exhibits less vectorial specificity than an attack on a carbonyl group (202). Because the immonium salts (200) are intermediate between an uncharged group and a carbocation, the equilibrium between oxazolidine (199) and Schiff salt is probably slower than a ring closure which is not disfavored.

Ajaconine (80) was the first example of a C,,-diterpenoid alkaloid containing an internal carbinolamine ether linkage between C-7 and C-20. An attempt by Dvornik and Edwards (86)to rearrange ajaconine in methanolic base resulted in a mixture that was not studied further. On the basis of chemical reactions and hydrogen-interaction theory, they concluded that a driving force for rearrangement of the internal carbinolamine ether is absent. The Canadian chemists (86) also mentioned that an entropy factor must favor the internal ether over the oxazolidine ring, and thus the C-7C-20 ethers should be more stable than the oxazolidine ring derivatives. Treatment of ajaconine with hydrochloric acid afforded a ternary im+

monium salt (203) instead of a protonated (-NH-) type salt. Treatment of the immonium salt (203) with base regenerated ajaconine (80) instead of 7a-hydroxyatisine (205), which would parallel the formation of atisine (4) from atisinium chloride (5). Transformation of ajaconium chloride to ajaconine is an example of a 6-exo-trig ring closure, which is a “favored” process according to Baldwin’s rules. The I3C-NMR spectral analysis of ajaconine in nonionic and ionic solvents indicated that in hydroxylic solvents the ether linkage of ajaconine ionizes and covalent solvation takes place (87). This observation accounted for the formation of the Schiff salt, with the resultant high pKa value (1 1.8) of ajaconine in aqueous solution-behavior which parallels that of atisine (pK, 12.5) and veatchine (pKa 11.5). These results suggested that ajaconine may be rearranged by refluxing in an ionic solvent to a compound in which the C-7-C-20 ether linkage is absent.

2.


204

153

205

Refluxing ajaconine in methanol afforded a mixture from which a new compound identified (87) as 7a-hydroxyisoatisine (82) was isolated. The structure of the latter was established by ‘H- and I3C-NMR spectroscopy. When ajaconine was refluxed in CH,OD under nitrogen, a mixture of C-19, C-20-deuterated ajaconine (206) and C- 19,C-2O-deuterated 7a-hydroxyisoatisine (207) was formed. Incorporation of deuterium in 206 and 297 indicated that ajaconine ionized and rearranged to 207 and that these species are in equilibrium in refluxing methanol.

The authors also suggested (87) a mechanism for this rearrangement in refluxing methanol. In alkaline solution the normal-type immonium species 208 closes to ajaconine (80) and not to 7%-hydroxyatisine(205) because the latter closure, being a “disfavored” 5-endo-trig process, is much slower

154

S . WILLIAM PELLETIER A N D NARESH V. MODY

than the “favored” 6-endo-trig closure of the normal-type immonium species to ajaconine. However, species 208 undergoes an isomerization to the isoimmonium salt 209 which is known in the case of the isomerization of atisine to isoatisine and of veatchine to garryine. The intermediate 209 closes to 7%-hydroxyisoatisine(82) in spite of the closure being partially disfavored because there is no faster process in competition with this ring closure.

205

80 Ajaconine

209

82

Veatchine acetate (210) was hydrolyzed to veatchine (1) in methanol a t room temperature without using any external base (152). This unusual hydrolysis was explained by participation of methoxide ion which was formed by opening of the oxazolidine ring by methanol. Diterpenoid alkaloid derivatives lacking the oxazolidine ring, such as dihydroatisine diacetate (211) and veatchine azomethine acetate (lo), failed to give compounds 212 and 78, respectively, in methanol under these conditions.

210

1 Veatchine

2.


78 R = H 211 R = Ac

155

10 R = AC 212 R = H

The hydrolysis of veatchine acetate to veatchine suggested an examination of the behavior of 7a-acetoxyatisine acetate (213) which was prepared from ajaconine (SO) via the corresponding imine. Acetylation of ajaconine with acetic anhydride and pyridine at room temperature afforded the triacetate salt 214 in quantitative yield. A Hofmann-type degradation of the triacetate salt was achieved by heating at reflux in chloroform to give the imine 215 in 95% yield. The latter reacted with ethylene oxide in acetic acid to afford 7a-acetoxyatisine acetate (213) in quantitative yield (152). When 213 was stirred in methanol at 25", a mixture of 7a-hydroxyisoatisine (82), ajaconine (SO), and their C-15 acetates (216 and 217) was formed. No starting material was detected after 36 hr. The formation of these products was explained on the basis of opening of the oxazolidine ring by methanol and formation of methoxide ion. The latter hydrolyzes the C-7 acetate group of 7-acetoxyatisine acetate. The resulting anion can close on the immonium

80

214

I

A CHCI,

213

215

156


“OH

80 R 216 R

= =

H Ajaconine AC

82 R = H 217 R = AC

species at C-20 to form ajaconine. And as mentioned earlier, the normaltype oxazolidine ring derivatives isomerize readily in methanol to the isotype oxazolidines. Recently, Pelletier, Nowacki, and Mody (155) reported that treatment of alkaloid imine derivatives with ethylene oxide in acetic acid or methanol afforded the oxazolidine ring-containing alkaloids in excellent yield. Treatment of lindheimerine (7) with ethylene oxide in acetic acid afforded ovatine (6) in 98% yield. Similarly, veatchine azomethine acetate (10) afforded veatchine acetate (210) in 97% yield. Formation of the oxazolidine ring in these

7 Lindheimerine

6 Ovatine

10

210 Veatchine acetate

compounds occurs via a “disfavored” 5-endo-trig ring closure. When methanol was used instead of acetic acid, 7 gave 6 in 90% yield within 3 hr. Under longer reaction times, 7 afforded only garryfoline (8) in a yield of 96%. Comparable results were also obtained with veatchine azomethine acetate (10). Under short reaction times, veatchine acetate (210) was produced and under longer reaction times, veatchine (1) was formed. Depending on the reaction time, treatment of atisine azomethine acetate (218) with ethylene oxide afforded either atisine acetate (219), atisine (4), or

2.


I R' = H, R 2 = OAc 10 R' = OAc, Rz = H

6 R'

= H,

157

R 2 = OAc Ovatine

210 R' = OAc, R 2 = H

1 R' = OH, R 2 = H Veatchine 8 R' = H, R2 = OH Garryfoline

isoatkine (75). Thus, in 3 hr atisine acetate was isolated, in 12 hr a mixture of atisine and isoatisine was formed, and in 24 hr only isoatisine was obtained.

218

4 Atisine

219 Atisine acetate

75 Isoatisine

Unlike ethylene oxide, oxetane reacted very slowly with the alkaloid imine derivatives to afford low yields of tetrahydro-l,3-oxazine derivatives. Treatment of veatchine azomethine acetate (10) with oxetane in acetic acid at 50" afforded the six-membered carbinolamine ether, homoveatchine acetate (220), in 25% yield. The latter was isolated as a mixture of C-20 epimers.

158


10

220

221

222

On the basis of these results, the authors designed (152) a reaction with imines in which either a five- or six-membered carbinolamine ether might be formed. Treatment of veatchine azomethine acetate with glycidol afforded compound 221 as the major product. The structure of 221 was established by 3C-NMR spectroscopy and confirmed by a single-crystal X-ray analysis. The presence of a five-membered ring containing compound 222 was not detected in the reaction mixture. In a similar reaction, atisine azomethine acetate (218) reacted with glycidol to yield a mixture of the C-20 epimers of compound 223. Surprisingly, treatment of ajaconine azomethine acetate (215) with glycidol gave the single C-20 epimer (224). This

218

223

L

“OAc

CH 3 215

224

2.

THE CHEMISTRY OF C2O-DITERPENOID ALKALOIDS

159

behavior suggested that the 7%-acetoxylgroup in 224 exerts a profound influence on the direction of closure of the carbinolamine ether linkage. In summary, certain reactions with diterpenoid alkaloid imines proceeded by a “disfavored” 5-endo-trigonal process, whereas in other cases, such as the reactions with glycidol, a “favored” 6-endo-trigonal process was followed. The Baldwin rules should be modified to accomodate the exceptional behavior of the tertiary immonium salts. Recently, examples of similar reactions demonstrating the violation of the Baldwin cyclization rules have been reported (156-158).

4a

4b

In 1970, Pradhan and Girijavallabhan (79)concluded that atisine in solution contains an equilibrium mixture of the C-20 epimers (4d and 4b), which are interconvertiable via a zwitterion. This conclusion was based on a ‘H-NMR study of atisine in different polar solvents. Later, Pelletier and Mody (154) reported that atisine in nonionic solvents exists as a mixture of C-20 epimers which do not interconvert via a zwitterion and that in ionic solvents atisine slowly isomerizes to isoatisine. This idea was supported by a I3C-NMR study of atisine in deuterated solvents. The results reported by Pelletier and Mody (154) were questioned by Pradhan (159)in 1978. The rebuttal paper was submitted prior to the publication of the X-ray crystallographic studies in which Pelletier and co-workers (30)reported additional evidence supporting their earlier conclusion. Recent work (36)on the structure of cuauchichicine further confirmed this conclusion. The normal-type oxazolidine ring of cuauchichicine does not exist as a mixture of C-20 epimers in solution. This unusual finding was confirmed (36)by a single-crystal X-ray analysis of cuauchichicine.

160


VI.

' 3C-NMR Spectroscopy of C,,-Diterpenoid

Alkaloids

Recent developments in instrumentation and techniques have made possible the application of 13C-NMR spectroscopy to the study of many natural products. 3C-NMR spectroscopy has become exceedingly important in the area of structure elucidation and synthesis of naturally occurring organic substances since its availability to organic chemists just over 10 years ago. Recently, 13C-NMR data have become important for the comparison of natural and synthetic compounds or degradation products. I3C-NMR spectral data have proved critically important in establishing the stereochemistry of compounds that are not available in crystalline form for X-ray analysis, such as atisine (4). The I3C-NMR spectra of diterpenoid alkaloids not only indicate the number and type of carbon atoms in the system but also reveal close structural and family resemblances and give detailed information about the sites of various functional groups. The usefulness of the I3C-NMR technique in solving difficult structural problems of complex diterpenoid alkaloids is reviewed here. In 1974, Japanese chemists (134) demonstrated the utility of 13C-NMR spectroscopy in the field of C,,-diterpenoid alkaloids. They determined the structures of miyaconine (145) and apomiyaconine (147), two rearrangement products of miyaconitine, by the aid of I3C-NMR spectroscopy. In 1976, Lamberton and co-workers (69, 70) demonstrated the use of 3C-NMR studies in elucidating the structures of several new C,,-diterpenoid alkaloids and their derivatives. The 3C-NMR spectra of several veatchine-type alkaloids and their derivatives [e.g., anopterine (51), anopteryl alcohol (52), tetraacetylanopteryl alcohol (54), triacetylanopteryl alcohol (61), compound 58, compound 59, anopterimine (70), anopterimine N-oxide (71), hydroxyanopterine (72), and dihydroanopterine (73)] were examined. The noise-decoupled and off-resonance proton-decoupled 3CNMR spectra of anopterine provided evidence for many unusual structural features and confirmed the structure of anopterine, which was established by a single-crystal X-ray analysis of tetraacetylanopteryl alcohol azomethine iodide (53). These 3C-NMR data were utilized in the structure determination of four new alkaloids (anopterimine, anopterimine N-oxide, hydroxyanopterine, and dihydroxyanopterine) isolated in small amounts from A . macleayanus and A , glandulosus. The power of the 3C-NMR spectroscopic technique was demonstrated (148-150) in the elucidation of the structures of some very complex natural products, the bisditerpenoid alkaloids, isolated from D. staphisagria. On the basis of 13C-NMR data of the known alkaloid, staphisine (185), the structures of seven new related alkaloids, staphidine (187), staphinine (1881, staphimine (189), staphigine (190), staphirine (191), staphisagnine (193),

'

'

'

2.


161

and staphisagrine (194),were determined. Partial chemical shift assignments for these alkaloids were presented in tabular form. A complete correlation of 3C- chemical shifts of staphisagnine and staphisagrine with those of staphisine and staphidine was also presented. In 1977, Pelletier and Mody (27) determined that atisine (4), veatchine (l), and related normal oxazolidine ring-containing derivatives exist as a mixture C-20 epimers in nonionic solvents with the help of 13C-NMR spectral data. Later, this claim was confirmed by a single-crystal X-ray analysis of veatchine. The same authors have also examined (154)the unusual behavior of the oxazolidine ring of atisine in ionic and nonionic solvents by 13C-NMR analysis and shown that the C-20 epimers of atisine are neither interconvertible via a zwitterion, as reported by Indian chemists (79), nor in equilibrium with each other. A comprehensive 13C-NMR study of the atisine and veatchine-type alkaloids as well as certain of their derivatives has been reported (28).The 3C-NMR spectra of atisine (4), atisinone (225),isoatisine (75), isoatisinone (226), dihydroatisine (78), dihydroatisine diacetate (211), atidine (79), atidine diacetate (227), atisine azomethine (228), atisine azomethine acetate (218), dihydroatisine azomethine (229), N-methyldihydroatisine azomethine (230), veatchine (l),garryine (2), dihydroveatchine (231), dihydroveatchine diacetate (232), veatchine azomethine (212), veatchine azomethine acetate (lo),dihydroveatchine azomethine (233); and N-methyldihydroveatchine azomethine (234) have been analyzed. Self-consistent assignments of nearly all the resonances were made in these compounds with the aid of single-frequency off-resonance proton decoupling techniques, additivity relationships, and the effectsinduced by certain structural changes.

225 Atisinone

227

226 Isoatisinone

228

162

S. WiLLIAM PELLETIER A N D NARESH V. MODY

231 R = H 232 R = Ac

229 R = H 230 R = CH3

233 R 234 R

=H = CH,

The I3C-NMR spectra of these compounds were analyzed to identify and distinguish skeletal features of the atisine and veatchine-type alkaloids for use in the structure elucidation of new C,,-diterpenoid alkaloids. The structures of two new C,,-diterpenoid alkaloids designated as ovatine (6) and lindheimerine (7), isolated from G . ovata var. Iindheimeri, have been elucidated (33)with the help of 13C-NMRspectroscopy. Similarly, the structure of dihydroajaconine (81) was also established (88) with this technique. Pelletier and Mody (87) have studied the behavior of ajaconine (88) in ionic and nonionic solvents with the aid of I3C-NMR spectroscopy. They established the structure of 7a-hydroxyisoatisine (82) and reported the 3CNMR spectra of 80,82, atisinium chloride (5), and ajaconium chloride (203). The stereochemistry of the C-16 methyl group and the oxazolidine ring in cuauchichicine was recently reassigned as a result of examining the I3CNMR spectra of isocuauchichicine (16) and its C-16 epimer (17). The oxazolidine ring of cuauchichicine was shown to exist as a single C-20 epimer in solution. Subsequently, the revised structure for cuauchichicine (15) was confirmed by X-ray analysis. 1 3C-NMR spectroscopy has proved to be a powerful technique for solving complex structural and conformational problems among the diterpenoid alkaloids. In the future we may expect an increasing use of this technique over traditional techniques such as IR, 'H-NMR, and MS for solving difficult structural problems in natural products chemistry. Unambiguous assignments of chemical shifts in these alkaloids will be useful in future biogenetic studies of C,,-diterpenoid alkaloids.

2.

163


VII. Mass Spectral Analysis of C,,-Diterpenoid Alkaloids The mass spectra of C,,-diterpenoid alkaloids are complex, and there is a paucity of information concerning their fragmentation patterns. The first systematic mass spectral analysis of these alkaloids was reported by Soviet chemists in 1970. Yunusov and colleagues (62) analyzed the mass spectra and their derivatives. of songorine (44),songoramine (47), napelline (M), Songorine and many related compounds give the parent ion as the base peak. In the case of some acetylated derivatives, M - 59 is the base peak. The fragmentation of these alkaloids occurs in several directions in contrast to the regular splitting pattern of the lycoctonine-type alkaloids. N-Methyl group-containing compounds exhibit a M + - 15 peak, which arises through the splitting of a methyl radical from the N-ethyl group. The cleavage of ring A is an important process in the mass spectra of songorine and related derivatives. The initial cleavage of the C-7-C-20 bond is common. The ions resulting from the cleavage of the C-7-C-20 bond of songorine are presented in pathways A and B. One of the strongest ions is m/e 298 (M' - 59), which is postulated to arise from the cleavage of the C-1-C-10 bond via the intermediate ion-radical with rnje 299. On the basis of the structure of the ionradical of mje 299, we have revised the structure of the M - 59 ion (Pathway A). Loss of rings C and D to form an ion with m/e 246 was considered to be the one-state transition. The latter was supported by a metastable peak. All the fragments containing ring C eliminate a formyl group or carbon monoxide. Formation of an ion with m/e 180 occurs directly from the molecular ion (Pathway B) by the expulsion of ring A, C, and D atoms. The metastable peak for rnje 180 ion was also observed. On the basis of the given pathway for the formation of rnje 180 ion, we have reassigned the structure of this ion. The fragmentation pattern of the mass spectrum of songorine diacetate (Pathway C) was not particularly revealing compared with that of songorine. The splitting off of the C- 15 acetyl group is manifested by the M - 43 peak (m/e 398). The strongest peak in the mass spectrum of songorine diacetate is the M f -59 peak (mje 382). This ion is further fragmented to a small extent with the expulsion of ketene or carbon monoxide as observed in the case of songorine. There are no major peaks in the lower mass region. For dihydrosongorine and its diacetate. major fragmentations were postulated to involve loss of ring D (Pathway D and E). In the case of dihydrosongorine, the ion-radical with rnje 301, in which loss of ring D has occurred, is the base peak, whereas in the diacetate mje 384 (loss of the C-1 acetoxyl group) is the strongest peak. Comparison of the mass spectrum of dihydrosongorine with that of its diacetate reveals that the presence of two acetate groups has some influence on the fragmentation patterns. Metastable peaks are observed for both transitions. +

+

+

/

44 Songorine M + 357 (100)

m / e 328 (16)

J

m / e 246

( I 3)

m/e

:Pathway A

270 (7)

2.

THE CHEMISTRY OF C2O-DITERPENOID ALKALOIDS

0 II ‘ZH5

&CH,

-

- -H

N’

0 II ‘ZH5

&CH,N‘

;!

OH

- -H

H,C’

OH

CH3

CH 3

Pathway B

m/e 441 (60)

m/e 382 (100)

\ 0 /I

m ’ e 398 ( 5 7 )

Pathway C

165

166


m/e 400 (8)

m/e 443 (13)

I

R R

=H

0

R = H mje 301 (100) R = Ac mle 343 (28)

nde 354 (26)

= Ac

m,’e 443 ( I 3)

I

J C,H

5-

Lq$

N/

C,H,--

I

CH 3 M

e

m

242 Pathway E

P

284

2.


167

The molecular ion peak is the strongest peak in the mass spectrum of songoramine (Pathway F). The fragmentation of songoramine begins with the cleavage of the carbinolamine ether linkage and ring A. The ion-radical with m/e 299, which arises from the explusion of acrolein, fragments further into an ion with mje 122. Both transitions are confirmed by metastable peaks. The ion with mje 299 also originates from the radical-ion with mle 327 by the loss of carbon monoxide, which was confirmed by the metastable peak. Some assignments for songorine and dihydrosongorine were confirmed by deuterium labeling of the hydroxyl groups and exocyclic methylene group. 0

0

CH 3 m/e 299 (46)

I C2H5

m r 122 (29)

m,'e 327 (10)

Pathway F

In 1978 Yunusov and colleagues (59) reported the mass spectral data of napelline and several of its derivatives. The fragmentation data for napelline. 1-acetylnapelline, 12-acetylnapelline, triacetylnapelline, anhydrohydroxyacetylnapelline, isoacetynapelline, dihydronapelline, and isonapelline were tabulated showing the intensities of various ion peaks. Sastry and Waller (89, 160) analyzed a deuterated trimethylsilyl derivative of ajaconine on a gas chromatograph-mass spectrometer (GC-MS) system. They found that the crystalline sample earlier identified as pure ajaconine was a mixture of five compounds. Peak 1 with retention time (R,) of 12.7 min had a molecular ion of 477. Peaks 2 ( R , = 17.3 min), 3 (R, = 21.0 rnin), and 4 (R,= 25.5 min), all with a molecular ion of 521 (503 for the nondeuterated TMS derivatives), accounted for the di-TMS derivatives of

168


ajaconine. Peak 5 ( R , = 27.8 min) had a molecular ion of 604 which indicated the presence of three deuterated TMS groups. Structural assignments for the five compounds were made on the basis of their fragmentation patterns.

VIII. Synthetic Studies A. TOTALSYNTHESIS OF OPTICALLY ACTIVE VEATCHINE In 1970, Professor Wiesner and co-workers (161)reported the first total synthesis of optically active veatchine (l),the major alkaloid of G. veatchii. An improved synthesis (162) of ketones 244 and 245 from compound 235 has been reported. These ketones had been synthesized (163) previously and transformed to veatchine. Lithium aluminium hydride reduction of 235 followed by mesylation afforded 236. The latter was oxidized with osmium tetroxide and sodium metaperiodate to yield the cyclobutanone 237. Treatment of 237 with acid afforded in 48% yield the ketoacid (238), which was esterified with diazomethane to 239. The latter was converted to the ketal240 by treatment with ethylene glycol and p-toluenesulfonic acid. Compound 240 was reduced with lithium aluminium hydride to the alcohol 241. This alcohol had been synthesized previously by Nagata and co-workers (164) by an entirely different route. The azide 242 was prepared in 80% yield by mesylation of 241 and treatment of the product with sodium azide. Lithium aluminium hydride reduction of 242 gave the primary amine, which was converted to the urethane 243 by treatment with ethyl chloroformate. The ketal group of 243 was removed by acidic hydrolysis and the resulting ketone was nitrosated with N,O, and sodium acetate. Decomposition of the nitrosourethane with sodium ethoxide in refluxing ethanol afforded the ketone 244 in 65% yield. The latter had been also synthesized previously by Japanese chemists (165). The ketone 244 was converted to the ketal 246 and the latter to 247

235

236 R = CHI 231 R = 0

2.


238 R = H 239 R = CH,

240 241 242 243

169

R=CO,CH, R=CH,OH R = CH,N, R = CH,NHCO,C,H,

by reduction with lithium in ammonia followed by acetylation. Deketalization of 247 afforded the desired ketone 245. The latter was identical with the optically active ketone prepared from veatchine. To complete the total synthesis of the optically active form of veatchine, the successful resolution of the synthetic racemic ketone 244 was accomplished. Compound 244 was reduced stereoselectively with sodium borohydride to give the alcohol 248. The latter was heated with succinic anhydride and pyridine in xylene to yield the racemic half-ester 249. Treatment of 249 with brucine afforded the diastereoisomeric brucine salts, which were separated by fractional crystallization. The separated salts were decomposed

R--

244 R = Ms 245 R = COCH,

248 R

=

H 0

249 R

= C(CH,),CO,H

'I

246 R 247 R

= =

MS COCH,

1 Veatchine

170

S. WILLIAM PELLETIER A N D NARESH V . MODY

and the half-esters were hydrolyzed. The resulting alcohols were oxidized to the respective ketones. The identity of the synthetic enantiomer with the same absolute configuration as the natural ketone 244 was established by mixture melting points and their ORD curves. The naturally derived ketone 244 was prepared for comparison purpose from 245 in the same manner, substituting acetylation for mesylation as mentioned earlier. The naturally derived ketone 245 had previously been prepared from veatchine by Vorbruggen and Djerassi (25). Since Canadian chemists had earlier published (163) work on the conversion of the degradation product 245 ofveatchine to garryine and veatchine, the total synthesis of the natural optically active form of these alkaloids is thus completed.

B. TOTALSYNTHESIS OF NAPELLINE In 1974, Wiesner and colleagues completed an elegant total synthesis of racemic napelline (34) (166). A series of model studies on this type of system was reported (167, 168). They developed (169)an efficient route to the intermediate ketolactam (250)and have used this compound to complete a formal synthesis of napelline (166, 170). The starting compound 251 was reduced to 252 with sodium borohydride. The latter was heated under reflux in 6% sulfuric acid in methanol to afford compound 253. Treatment of the latter with maleic anhydride at 170" for 3 hr afforded compound 254. Bisdecarboxylation of 254 with dicarbonyl bistriphenylphosphinenickel in anhydrous diglyme under nitrogen at reflux temperature for 6 hr afforded the olefin 255 in 69% yield (171). The latter was reduced with lithium aluminium hydride to the primary alcohol 256, which was oxidized to the aldehyde 257 with N,N-dicyclohexylcarbodiimide, dimethyl sulfoxide and pyridine in dry benzene. Treatment of the aldehyde 257 with an excess of the Grignard reagent prepared from l-bromo-3benzyloxybutane afforded a mixture of diastereoisomers represented by the structure 258.

250

34 Napelline

2.

THE CHEMISTRY OF C2,-DITERPENOID ALKALOIDS

;-"

COZCH,

0

OCH,

OCH,

%COzCH3

QCOzCH3

HO

251

@. oc3H

171

252

253

0

0 254

258

255 R = CO,CH, 256 R = CHzOH 257 R = CHO

The mixture 258 was converted to the unstable benzenesulfonyl aziridine 259 by treatment with an excess of benzenesulfonyl azide in benzene. Acetolysis of 259 with acetic acid and sodium acetate at room temperature for several days afforded the crystalline mixture of diastereoisomers represented by the formula 260. The aziridine rearrangement was regiospecific and 260 was the only product detected during this rearrangement. Lithium aluminium hydride reduction of 260 followed by acetylation yielded the mixture 261 in 85% yield. Selective hydrolysis of 261 afforded 262 in quantitative yield. The diastereoisomeric mixture 262 was converted into the diols 263 by hydrogenolysis. The diol mixture was oxidized with chromium trioxide OCH, I

C,H,CH,O

CH,

ORZ

260 R' = H, R2 = Ac, R 3 = SO,C,H,. 261 R' = R z = R3 = AC 262 R' = R 2 = Ac. R3 = H

172


in pyridine to afford the epimeric diketones 264. An aldol condensation of the mixture of the two diketones 264 in refluxing methanolic potassium carbonate gave the crystalline mixture of two epimers 265 in 88% yield. Photoaddition of vinyl acetate to 265 yielded the two epimers of compound 266. 0%

OCH,

HO CH, 263

264

OCH

CH,

0

,

0 OAc

265

266

This mixture was saponified with methanolic potassium hydroxide to give the two epimers of 267 in quantitative yield. By enol acetylation, 267 was converted to 268 which in turn was oxidized by osmium tetroxide and periodate to the noraldehydes 269. The mixture 269 was converted to 270 via oxidation, esterification, and mild alkaline hydrolysis. The hydroxyesters 270 were oxidized by the Jones' method to afford the single crystalline diketoester 271. Ketalization of 271 yielded the ketal 272 in quantitative ?CH3

?CH, R

I

I

Ac-1--r*

CH, 267 268 269 270

R' R' R' R'

H, RZ = CH,CHO R 2 = CH=CHOAc = Ac, R 2 = CHO = H, RZ = C02CH, =

= Ac,

CH, 271 R = O 272 R

=

CH,

data

Refs. 18, 25,26,34-36

202


Isogarryfoline C,,H,,NO,; MW 343 mp 140-144.; {%ID-57 (Chf) Garrya laurifolia Chemically correlated with garryfoline; Chemical and spectral data Refs. 18, 2 5 , 2 6 , 3 3 - 3 6 , 3 9

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